Phenylpiperidines and Phenylpyrrolidines

ABSTRACT

Substituted phenylpiperidines and phenylpyrrolidines of formula (I), compositions containing them, and methods of making and using them to treat histamine-mediated conditions.

CROSS:-REFERENCE TO RELATED APPLICATIONS

Provisional Application No. 60/420,494, filed Oct. 23, 2002, herebyincorporated by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The research and development of the invention described below was notfederally sponsored.

FIELD OF THE INVENTION

The present invention relates to phenylpiperidines andphenylpyrrolidines, their synthesis and their use, for example, for thetreatment of disorders and conditions mediated by the histaminereceptor.

BACKGROUND OF THE INVENTION

Histamine {2-(imidazol-4-yl)ethylamine} is a transmitter substance.Histamine exerts a physiological effect via multiple distinct G-proteincoupled receptors. It plays a role in immediate hypersensitivityreactions and is released from mast cells following antigen IgE antibodyinteraction. The actions of released histamine on the vasculature andsmooth muscle system account for the symptoms of the allergic response.These actions occur at the H₁ receptor (Ash, A. S. F. and Schild, H. O.,Br. J. Pharmac. Chemother. 1966, 27:427-439) and are blocked by theclassical antihistamines (e.g. diphenhydramine). Histamine is also animportant regulator of gastric acid secretion through its action onparietal cells. These effects of histamine are mediated via the H₂receptor (Black, J. W. et al., Nature 1972, 236:385-390) and are blockedby H₂ receptor antagonists (e.g. cimetidine). The third histaminereceptor —H₃— was first described as a presynaptic autoreceptor in thecentral nervous system (CNS) (Arrang, J.-M. et al., Nature 1983,302:832-837) controlling the synthesis and release of histamine. Recentevidence has emerged showing that the H₃ receptors are also locatedpresynaptically as heteroreceptors on serotonergic, noradrenergic,dopaminergic, cholinergic, and GABAergic (gamma-aminobutyric acidcontaining) neurons. These H₃ receptors have also recently beenidentified in peripheral tissues such as vascular smooth muscle.Consequently there are many potential therapeutic applications forhistamine H₃ agonists, antagonists, and inverse agonists. (See: “TheHistamine H ₃ Receptor-A Target for New Drugs”, Leurs, R., andTimmerman, H., (Eds.), Elsevier, 1998; Morisset, S. et al., Nature 2000,408:860-864.) A fourth histamine receptor —H₄— was recently described byOda, T. et al. (J. Biol. Chem. 2000, 275(47):36781-36786).

The potential use of histamine H₃ agonists in sleep/wake andarousal/vigilance disorders is suggested based on animal studies (Lin,J.:-S. et al., Brain Res. 1990, 523:325-330; Monti, J. M. et al., Eur.J. Pharmacol. 1991, 205:283-287). Their use in the treatment of migrainehas also been suggested (McLeod, R. L. et al., Soc. Neurosci. Abstr.1996, 22:2010) based on their ability to inhibit neurogenicinflammation. Other applications could be a protective role inmyocardial ischemia and hypertension where blockade of norepinephrinerelease is beneficial (Imamura, M. et al., J. Pharmacol. Exp. Ther.1994, 271(3):1259-1266). It has been suggested that histamine H₃agonists may be beneficial in asthma due to their ability to reducenon-adrenergic non-cholinergic (NANC) neurotransmission in airways andto reduce microvascular leakage (Ichinose, M. and Barnes, P. J., Eur. J.Pharmacol. 1989, 174:49-55).

Several indications for histamine H₃ antagonists and inverse agonistshave similarly been proposed based on animal pharmacology experimentswith known histamine H₃ antagonists (e.g. thioperamide). These includedementia, Alzheimer's disease (Panula, P. et al., Soc. Neurosci. Abstr.1995, 21:1977), epilepsy (Yokoyama, H. et al., Eur. J. Pharmacol. 1993,234:129-133) narcolepsy, eating disorders (Machidori, H. et al., BrainRes. 1992, 590:180-186), motion sickness, vertigo, attention deficithyperactivity disorders (ADHD), learning and memory (Barnes, J. C. etal., Soc. Neurosci. Abstr. 1993, 19:1813), and schizophrenia (Schlicker,E. and Marr, I., Naunyn-Schmiedeberg's Arch. Pharmacol. 1996,353:290-294). (Also see: Stark, H. et al., Drugs Future 1996,21(5):507-520; and Leurs, R. et al., Prog. Drug Res. 1995, 45:107-165and references cited therein.) Histamine H₃ antagonists, alone or incombination with a histamine H₁ antagonist, are reported to be usefulfor the treatment of upper airway allergic response (U.S. Pat. Nos.5,217,986; 5,352,707 and 5,869,479). Recently, a histamine H₃ antagonist(GT-2331) was identified and is being developed by Gliatech Inc.(Gliatech Inc. Press Release Nov. 5, 1998; Bioworld Today, Mar. 2, 1999)for the treatment of CNS disorders.

As noted, the literature related to histamine H₃ ligands has beencomprehensively reviewed (“The Histamine H ₃ Receptor-A Target for NewDrugs”, Leurs, R. and Timmerman, H., (Eds.), Elsevier, 1998). Withinthis reference the medicinal chemistry of histamine H₃ agonists andantagonists was reviewed (see Krause, M. et al., and Phillips, J. G. andAli, S. M., respectively). The importance of an imidazole moietycontaining only a single substitution in the 4-position was notedtogether with the deleterious effects of additional substitution onactivity. Particularly, methylation of the imidazole ring at any of theremaining unsubstituted positions was reported to strongly decreaseactivity. Additional publications support the hypothesis that animidazole function is essential for high affinity histamine H₃ receptorligands (see Ali, S. M. et al., J. Med. Chem. 1999, 42:903-909, andStark, H. et al., and references cited therein). However manyimidazole-containing compounds are substrates for histamine methyltransferase, the major histamine metabolizing enzyme in humans, whichleads to shortened half-lives and lower bioavailability (see Rouleau, A.et al., J. Pharmacol. Exp. Ther. 1997, 281(3):1085-1094). In addition,imidazole-containing drugs, via their interaction with the cytochromeP450 monooxygenase system, can be targets of unfavorablebiotransformations due to enzyme induction or enzyme inhibition (see:Kapetanovic, I. M. and Kupferberg, H. J., Drug Metab. Dispos. 1984,12(5):560-564; Sheets, J. J. and Mason, J. I., Drug Metab. Dispos. 1984,12(5):603-606; Back, D. J. and Tjia, J. F., Br. J. Pharmacol. 1985,85:121-126; Lavrijsen, K. et al., Biochem. Pharmacol. 1986,35(11):1867-1878; Albengres, E. et al., Drug Safety 1998, 18(2):83-97).The poor blood brain barrier penetration of earlier histamine H₃receptor ligands may also be associated with the imidazole fragment(Ganellin, C. R. et al., Arch. Pharm. Pharm. Med. Chem. (Weinheim, Ger.)1998, 331:395-404).

More recently, several publications have described histamine H₃ ligandsthat do not contain an imidazole moiety, for example: Ganellin, C. R. etal.; Walczynski, K. et al., Arch. Pharm. Pharm. Med. Chem. (Weinheim,Ger.) 1999, 332:389-398; Walczynski, K. et al., Farmaco 1999,54:684-694; Linney, I. D. et al., J. Med. Chem. 2000, 43:2362-2370;Tozer, M. J. and Kalindjian, S. B., Exp. Opin. Ther. Patents 2000,10:1045-1055; U.S. Pat. No. 5,352,707; PCT Application WO 99/42458, Aug.26, 1999; PCT Application WO 02/076925; and European Patent Application0978512, Feb. 9, 2000.

The compounds of the present invention do not contain the imidazolemoiety, and its inherent liabilities, and yet maintain potency at thehuman H₃ receptor as determined by receptor binding to the humanhistamine H₃ receptor (see Lovenberg, T. W. et al., Mol. Pharmacol.1999, 55:1101-1107). Screening using the human receptor is particularlyimportant for the identification of new therapies for the treatment ofhuman disease. Conventional binding assays are determined using ratsynaptosomes (Garbarg, M. et al., J. Pharmacol. Exp. Ther. 1992,263(1):304-310), rat cortical membranes (West, R. E. et al., Mol.Pharmacol. 1990, 38:610-613), and guinea pig brain (Korte, A. et al.,Biochem. Biophys. Res. Commun. 1990, 168(3):979-986). Only limitedstudies have been performed previously using human tissue but theseallude to significant differences in the pharmacology of rodent andprimate receptors (West, R. E. et al., Eur. J. Pharmacol. 1999,377:233-239).

We now describe a series of phenylpiperidines and phenylpyrrolidineswith the ability to modulate the activity of the histamine receptor,specifically the H₃ receptor, without the inherent problems associatedwith the presence of an imidazolyl moiety.

SUMMARY OF THE INVENTION

The present invention is directed to pharmaceutically activephenylpiperidines and phenylpyrrolidines, methods of making them, andmethods of using them. The invention features a compound of formula (I):

wherein

-   L is a direct bond, or an optionally C₁₋₄alkyl substituted radical    selected from the group consisting of C₁₋₄alkylene or C₃₋₄alkenylene    wherein NR¹R² is attached to an Sp³ hybridized carbon,    C₃₋₄alkynylene wherein NR¹R² is attached to an Sp³ hybridized    carbon, C₂₋₄alkylidene wherein NR¹R² is attached to an Sp³    hybridized carbon, aryloxy wherein NR¹R² is not attached to the    oxygen, arylthio wherein NR¹R² is not attached to the sulfur,    C₂₋₄alkoxy wherein NR¹R² is not attached to the oxygen or a carbon    attached to the oxygen, C₂₋₄alkylthio wherein NR¹R² is not attached    to the sulfur or a carbon attached to the sulfur, and    —C₂₋₃alkyl-X—C₁₋₂alkyl- wherein X is O, S or NH and wherein NR¹R² is    not attached to a carbon attached to X;    p is 0, 1 or 2;    q is 1 or 2; provided that 2≦p+q≦4;-   R¹ is a substituent independently selected from the group consisting    of hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₉ carbocyclyl, 3-12    membered heterocyclyl (preferably 5-9 or 5-8-membered heterocyclyl),    phenyl, (5-9-membered heterocyclyl)C₁₋₆ alkylene, and (phenyl)C₁₋₆    alkylene;-   R² is a substituent independently selected from the group consisting    of C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₉ membered carbocyclyl, 3-12    membered heterocyclyl (preferably 5-9 or 5-8-membered heterocyclyl),    phenyl, (5-9-membered heterocyclyl)C₁₋₆ alkylene, and (phenyl)C₁₋₆    alkylene;-   or R¹ and R² taken together with the nitrogen to which they are    attached form a saturated 3-13 membered N:-linked heterocyclyl,    wherein, in addition to the N:-linking nitrogen, the 3-13 membered    heterocyclyl may optionally contain between 1 and 3 additional    heteroatoms independently selected from O, S, and NH;-   wherein R¹ and R² are optionally and independently substituted with    1-3 substituents selected from the group consisting of    tert-butyloxycarbonyl, hydroxy, halo, nitro, amino, cyano,    carboxamide, C₁₋₆ alkyl, C₁₋₆ acyl, 5-9-membered heterocyclyl,    —N(C₁₋₆ alkyl)(5-9 membered heterocyclyl), —NH(5-9 membered    heterocyclyl), —O(5-9 membered heterocyclyl), (5-9 membered    heterocyclyl)C₁₋₃ alkylene, C₁₋₂-hydroxyalkylene, C₁₋₆ alkoxy, (C₃₋₆    cycloalkyl):-O—, phenyl, (phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃    alkylene-O—; and wherein each of the preceding substituents of R¹    and R² may optionally have between 1 and 3 substituents    independently selected from the group consisting of trifluoromethyl,    halo, nitro, cyano, hydroxy, and C₁₋₃ alkyl;-   one of R³, R⁴ and R⁵ is G and the other two independently are    hydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl, methyl, or    C₁₋₃ alkoxy    G is L²Q;-   L² is unbranched —(CH₂)_(n)— wherein n is an integer from 1 to 7    (preferably n is 1 to 4, more preferably n is 1);-   Q is NR⁸R⁹ wherein R⁸ is independently selected from hydrogen, C₁₋₆    alkyl, C₃₋₆ alkenyl, C₃₋₉ carbocyclyl, 3-12 membered heterocyclyl    (preferably 5-9 or 5-8-membered heterocyclyl), phenyl, (5-9-membered    heterocyclyl)C₁₋₆ alkylene, and (phenyl)C₁₋₆ alkylene; and R⁹ is    independently selected from C₁₋₆ alkyl, C₃₋₆ alkenyl, 3-9 membered    carbocyclyl, 3-13 membered heterocyclyl (preferably 5-9 or    5-8-membered heterocyclyl), phenyl, (5-9-membered heterocyclyl)C₁₋₆    alkylene, and (phenyl)C₁₋₆ alkylene; or Q is a saturated 3-15    membered N:-linked heterocyclyl, wherein, in addition to the    N:-linking nitrogen, the 3-15 membered heterocyclyl may optionally    contain between 1 and 4 additional heteroatoms independently    selected from O, S, and NH;-   wherein Q is optionally substituted with 1-3 substituents selected    (in addition to the preceding paragraph) from the group consisting    of tert-butyloxycarbonyl, hydroxy, halo, nitro, amino, cyano,    carboxamide, C₁₋₆ alkyl, C₁₋₆ acyl, 5-9-membered heterocyclyl,    —N(C₁₋₆ alkyl)(5-9 membered heterocyclyl), —NH(5-9 membered    heterocyclyl), —O(5-9 membered heterocyclyl), (5-9 membered    heterocyclyl)C₁₋₃ alkylene, C₁₋₂-hydroxyalkylene, C₁₋₆ alkoxy, (C₃₋₆    cycloalkyl):-O—, phenyl, (phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃    alkylene-O—; and where said substituent groups of Q may optionally    have between 1 and 3 substituents independently selected from    trifluoromethyl, halo, nitro, cyano, hydroxy, and C₁₋₃ alkyl;    R^(a) are independently C₁₋₃ alkyl, trifluoromethyl;    m is 0, 1, 2 or 3; and-   wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl,    cycloalkyl, carbocyclyl, and aryl groups may each be independently    and optionally substituted with between 1 and 3 substituents    independently selected from methoxy, halo, amino, nitro, hydroxy,    and C₁₋₃ alkyl;-   or a pharmaceutically acceptable salt, ester, tautomer, solvate or    amide thereof.

The invention also features a pharmaceutical composition comprising acompound of the invention and a pharmaceutically acceptable carrier; andmethods of preparing or formulating such compositions. A composition ofthe invention may further include more than one compound of theinvention, or a combination therapy (combination formulation orcombination of differently formulated active agents).

The invention also provides methods of treating certain conditions anddiseases, each of which methods includes administering a therapeuticallyeffective (or jointly effective) amount of a compound or composition ofthe invention to a subject in need of such treatment. The disclosedcompounds are useful in methods for treating or preventing neurologicdisorders including sleep/wake and arousal/vigilance disorders (e.g.insomnia and jet lag), attention deficit hyperactivity disorders (ADHD),learning and memory disorders, cognitive dysfunction, migraine,neurogenic inflammation, dementia, mild cognitive impairment(pre-dementia), Alzheimer's disease, epilepsy, narcolepsy, eatingdisorders, obesity, motion sickness, vertigo, schizophrenia, substanceabuse, bipolar disorders, manic disorders and depression, as well asother histamine H₃ receptor mediated disorders such as upper airwayallergic response, asthma, itch, nasal congestion and allergic rhinitisin a subject in need thereof. For example, the invention featuresmethods for preventing, inhibiting the progression of, or treating upperairway allergic response, asthma, itch, nasal congestion and allergicrhinitis.

In yet another embodiment, the disclosed compounds may be used in acombination therapy method including administering a jointly effectivedose of an H₃ antagonist and administering a jointly effective dose of ahistamine H₁ antagonist, such as loratidine (CLARITIN™), desloratidine(CLARINEX™), fexofenadine (ALLEGRA™) and cetirizine (ZYRTEC™), for thetreatment of allergic rhinitis, nasal congestion, and allergiccongestion.

In yet another embodiment, the disclosed compounds may be used in acombination therapy method, including administering a jointly effectivedose of an H₃ antagonist and administering a jointly effective dose of aneurotransmitter re-uptake blocker, such as a selective serotoninre-uptake inhibitor (SSRI) or a non-selective serotonin, dopamine ornorepinephrine re-uptake inhibitor, including fluoxetine (PROZAC™),sertraline (ZOLOFT™), paroxetine (PAXIL™) and amitryptyline, for thetreatment of depression, mood disorders or schizophrenia.

Additional features and advantages of the invention will become apparentfrom the detailed description and examples below, and the appendedclaims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides phenylpiperidine and phenylpyrrolidinecompounds useful for the treatment of disorders and conditions modulatedby a histamine receptor.

A. TERMS

Certain terms are defined below and by their usage throughout thisdisclosure.

As used herein, “C_(a-b)” (where a and b are integers) refers to aradical containing from a to b carbon atoms inclusive. For example, C₁₋₃denotes a radical containing 1, 2 or 3 carbon atoms.

As used herein, “halo” or “halogen” shall mean monovalent radicals ofchlorine, bromine, fluorine and iodine.

As used herein, the term “alkyl”, whether used alone or as part of asubstituent group, shall include straight and branched saturated carbonchains. For example, alkyl radicals include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like.Unless otherwise noted, “lower” when used with alkyl means a carbonchain composition of 1-4 carbon atoms. “Alkylene” refers to a divalenthydrocarbyl group, such as methylene (—CH₂—), ethylene (—CH₂—CH₂—) orpropylene (—CH₂CH₂CH₂—), and so on.

As used herein, unless otherwise noted, “alkenyl” shall mean an alkylenegroup with at least two hydrogen atoms replaced with a pi bond to form acarbon-carbon double bond, such as propenyl, butenyl, pentenyl, and soon. Where the alkenyl group is R⁸ or R⁹, the open radical (point ofattachment to the rest of the molecule) is on an Sp³ carbon, asillustrated by allyl, and the double bond or bonds is therefore at leastalpha (if not beta, gamma, etc.) to the open radical.

As used herein, “alkylidene” refers to a saturated or unsaturated,branched, straight-chain or cyclic divalent hydrocarbon radical derivedby removal of two hydrogen atoms from the same carbon atom of a parentalkane, alkene or alkyne. The divalent radical center forms a doublebond with a single atom on the rest of the molecule. Typical alkylideneradicals include, but are not limited to, ethanylidene; propylidenessuch as propan-1-ylidene, propan-2-ylidene, cyclopropan-1-ylidene;butylidenes such as butan-1-ylidene, butan-2-ylidene,2-methyl-propan-1-ylidene, cyclobutan-1-ylidene; and the like.

As used herein, unless otherwise noted, “alkoxy” shall denote an oxygenether radical of the above-described straight or branched chain alkylgroups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy,n-hexyloxy and the like.

As used herein, unless otherwise noted, “cycloalkyl” shall denote athree- to eight-membered, saturated monocyclic carbocyclic ringstructure. Suitable examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used herein, unless otherwise noted, “cycloalkenyl” shall denote athree- to eight-membered, partially unsaturated, monocyclic, carbocyclicring structure, wherein the ring structure contains at least one doublebond. Suitable examples include cyclohexenyl, cyclopentenyl,cycloheptenyl, cyclooctenyl, cyclohex-1,3-dienyl and the like.

As used herein, unless otherwise noted, “aryl” shall refer tocarbocyclic aromatic groups such as phenyl, naphthyl, and the like.Divalent radicals include phenylene (—C₆H₄—) which is preferablyphen-1,4-diyl, but may also be phen-1,3-diyl.

As used herein, unless otherwise noted, “aralkyl” shall mean any alkylgroup substituted with an aryl group such as phenyl, naphthyl, and thelike. Examples of aralkyls include benzyl, phenethyl, and phenylpropyl.

As used herein, unless otherwise noted, “carbocyclyl” shall mean anycyclic group consisting of 3-15 carbon atoms, and preferably 6-9 carbonatoms, in the skeleton ring or rings, if the carbocycle is a fused orspiro bicyclic or tricyclic group. A carbocycle may be saturated,unsaturated, partially unsaturated, or aromatic. Examples includecycloalkyl, cycloalkenyl, cycloalkynyl; specific examples includephenyl, benzyl, indanyl, and biphenyl. A carbocycle may havesubstituents that are not carbon or hydrogen, such as hydroxy, halo,halomethyl, and so on as provided elsewhere herein.

As used herein, unless otherwise noted, the terms “heterocycle”,“heterocyclyl” and “heterocyclo” shall denote any three- tofifteen-membered monocyclic, nine- or ten-membered bicyclic or thirteen-or fourteen-membered tricyclic ring structure containing at least oneheteroatom moiety selected from the group consisting of NH, O, SO, SO₂,(C═O), and S, and preferably NH, O, or S, optionally containing one tofour additional heteroatoms in each ring. In some embodiments, theheterocyclyl contains between 1 and 4 or between 1 and 2 additionalheteroatoms. Unless otherwise specified, a heterocyclyl may besaturated, partially unsaturated, aromatic or partially aromatic. Theheterocyclyl group may be attached at any heteroatom or carbon atom thatresults in the creation of a stable structure.

Exemplary monocyclic heterocyclic groups can include pyrrolidinyl,pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl,imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl,isoxazolyl, thiazaolyl, thiadiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, hexahydroazepinyl,4-piperidinyl, pyridyl, N:-oxo-pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl,thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dixolane andtetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl,thiiranyl, triazinyl, triazolyl, tetrazolyl, azatricyclodecanyl,1,4,7,10-tetraoxa-13-aza-cyclopentadecanyl, azetidinyl and the like.

For example, where Q is a saturated 3-15 membered N:-linkedheterocyclyl, Q necessarily contains at least one nitrogen, and thecarbon atoms are Sp³ hybridized. Where Q is a fused bicyclicheterocyclyl, the carbon atom of the ring linked to L is Sp³ hybridized,provided the adjacent ring (and the common carbon atoms) may be Sp²,such as an indanyl where one of the carbon atoms has been replaced withnitrogen.

In general, exemplary bicyclic heterocyclyls include benzthiazolyl,benzoxazolyl, benzoxazinyl, benzothienyl, quinuclidinyl, quinolinyl,quinolinyl:-N:-oxide, tetrahydroisoquinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl,coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopridyl,furopyridinyl (such as furo{2,3-c}pyridinyl, furo{3,1-b}pyridinyl), orfuro{2,3-b}pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl (such as1,2,3,4-tetrahydroquinolinyl), tetrahydroisoquinolinyl(such as1,2,3,4-tetrahydroisoquiunolinyl), benzisothiazolyl, benzisoxazolyl,benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl,benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone,dihydrobenzopyranyl, indolinyl, isoindolyl, tetrahydroindoazolyl (suchas 4,5,6,7-tetrahydroindazolyl), isochromanyl, isoindolinyl,naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl,quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl,thienothienyl,

and the like.

Exemplary tricyclic heterocylclic groups include acridinyl,phenoxazinyl, phenazinyl, phenothiazinyl, carbozolyl, perminidinyl,phenanthrolinyl, carbolinyl, naphthothienyl, thianthrenyl, and the like.

Preferred heterocyclyl groups include morpholinyl, thiomorpholinyl,piperidinyl, piperazinyl, pyrrolidinyl, pyrimidinyl, pyridyl, pyrrolyl,imidazolyl, oxazolyl, isoxazolyl, acridinyl, azepinyl,hexahydroazepinyl, azatricyclodecanyl,1,4,7,10-tetraoxa-13-aza-cyclopentadecanyl, azetidinyl, indolyl,isoindolyl, thiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 1,3,4-trihydroisoquinolinyl,4,5,6,7-tetrahydroindadolyl, benzoxazinyl, benzoaxzolyl, benzthiazolyl,benzimidazolyl, tetrazolyl, oxadiazolyl,

As used herein, unless otherwise noted, the term “heterocyclyl-alkyl” or“heterocyclyl-alkylene” shall denote any alkyl group substituted with aheterocyclyl group, wherein the heterocyclyl-alkyl group is boundthrough the alkyl portion to the central part of the molecule. Suitableexamples of heterocyclyl-alkyl groups include, but are not limited topiperidinylmethyl, pyrrolidinylmethyl, piperidinylethyl,piperazinylmethyl, pyrrolylbutyl, piperidinylisobutyl, pyridylmethyl,pyrimidylethyl, and the like.

When a particular group is “substituted” (e.g., alkyl, alkylene,cycloalkyl, aryl, heterocyclyl, heteroaryl), that group may have one ormore substituents, preferably from one to five substituents, morepreferably from one to three substituents, most preferably from one totwo substituents, independently selected from the list of substituents.

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenyl(alkyl)amido(alkyl)” substituent refers to agroup of the formula

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes prevention, inhibition of onset, oralleviation of the symptoms of the disease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

Abbreviations used in the specification, particularly in the Schemes andExamples, are as follows: DBAD = Di-tert-butyl azodicarboxylate DCE =1,2-dichloroethane DCM = Dichloromethane DEAD = Diethyl azodicarboxylateDMA = N,N-dimethylacetamide DMAP = 4-N,N-dimethylamino- pyridine DME =1,2-dimethoxyethane DMF = Dimethylformamide DMSO = Dimethylsulfoxide RT= Room temperature TEA = Triethylamine TFA = Trifluoroacetic acid THF =Tetrahydrofuran

B. COMPOUNDS

The invention features a compound of formula (I):

wherein

-   L is a direct bond, or an optionally C₁₋₄alkyl substituted radical    selected from the group consisting of C₁₋₄alkylene or C₃₋₄alkenylene    wherein NR¹R² is attached to an Sp³ hybridized carbon,    C₃₋₄alkynylene wherein NR¹R² is attached to an Sp³ hybridized    carbon, C₂₋₄alkylidene wherein NR¹R² is attached to an Sp³    hybridized carbon, aryloxy wherein NR¹R² is not attached to the    oxygen, arylthio wherein NR¹R² is not attached to the sulfur,    C₂₋₄alkoxy wherein NR¹R² is not attached to the oxygen or a carbon    attached to the oxygen, C₂₋₄alkylthio wherein NR¹R² is not attached    to the sulfur or a carbon attached to the sulfur, and    —C₂₋₃alkyl-XC₁₋₂alkyl- wherein X is O, S or NH and wherein NR¹R² is    not attached to a carbon attached to X;    p is 0, 1 or 2;    q is 1 or 2; provided that 2≦p+q≦4;-   R¹ and R² are independently selected from hydrogen, C₁₋₃ alkyl,    allyl, C₃₋₈ cycloalkyl, 5-9 membered heterocyclyl, phenyl, and    (phenyl)C₁₋₃ alkylene, or taken together with the nitrogen to which    they are attached, they form a non-aromatic 4-13 membered    heterocyclyl optionally including up to two additional heteroatoms    independently selected from O, S, and NH; and wherein R¹ and R² are    optionally and independently substituted with substitutents selected    from the group consisting of trifluoromethyl, halo, nitro, cyano,    hydroxy, and C₁₋₃ alkyl;-   one of R³, R⁴ and R⁵ is G and the other two independently are    hydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl, methyl, or    C₁₋₃ alkoxy    G is L²Q;-   L² is unbranched —(CH₂)_(n)— wherein n is an integer from 1 to 7    (preferably n is 1 to 4, more preferably n is 1);-   Q is NR⁸R⁹ wherein R⁸ is independently selected from hydrogen, C₁₋₆    alkyl, C₃₋₆ alkenyl, C₄₋₉ carbocyclyl, 3-12 membered heterocyclyl    (preferably 5-9 or 5-8-membered heterocyclyl), phenyl, (5-9-membered    heterocyclyl)C₁₋₆ alkylene, and (phenyl)C₁₋₆ alkylene; and R⁹ is    independently selected from C₁₋₆ alkyl, C₃₋₆ alkenyl, C₄₋₉ membered    carbocyclyl, 3-12 membered heterocyclyl (preferably 5-9 or    5-8-membered heterocyclyl), phenyl, (5-9-membered heterocyclyl)C₁₋₆    alkylene, and (phenyl)C₁₋₆ alkylene; or Q is a saturated 3-15    membered N:-linked heterocyclyl, wherein, in addition to the    N:-linking nitrogen, the 3-15 membered heterocyclyl may optionally    contain between 1 and 4 additional heteroatoms independently    selected from O, S, and NH;-   and wherein Q is optionally substituted with 1-3 substituents    selected (in addition to the preceding paragraph) from the group    consisting of tert-butyloxycarbonyl, hydroxy, halo, nitro, amino,    cyano, carboxamide, C₁₋₆ alkyl, C₁₋₆ acyl, 5-9-membered    heterocyclyl, —N(C₁₋₆ alkyl)(5-9 membered heterocyclyl), —NH(5-9    membered heterocyclyl), —O(5-9 membered heterocyclyl), (5-9 membered    heterocyclyl)C₁₋₃ alkylene, C₁₋₂-hydroxyalkylene, C₁₋₆ alkoxy, (C₃₋₆    cycloalkyl):-O—, phenyl, (phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃    alkylene-O—; and where said substituent groups of Q may optionally    have between 1 and 3 substituents independently selected from    trifluoromethyl, halo, nitro, cyano, hydroxy, and C₁₋₃ alkyl;    R^(a) are independently C₁₋₃ alkyl, trifluoromethyl;    m is 0, 1, 2 or 3; and-   wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl,    cycloalkyl, carbocyclyl, and aryl groups may each be independently    and optionally substituted with between 1 and 3 substituents    independently selected from methoxy, halo, amino, nitro, hydroxyl,    and C₁₋₃ alkyl;-   or a pharmaceutically acceptable salt, ester, tautomer, solvate or    amide thereof.

The invention features compounds of formula (I). Preferred compoundsinclude those wherein:

(a) NR¹R² taken together form substituted or unsubstituted morpholinyl,thiomorpholinyl, piperidinyl, methylpiperidinyl, piperazinyl,N:-methylpiperazinyl, dimethylamino, pyrrolidinyl, azatricyclodecanyl,cyclohexylmethylamino, methylphenethylamino, pyridylamino, anilino,diethylamino, methylethylamino, ethylpropylamino, or dipropylamino;

(b) NR¹R² taken together form a saturated N:-linked nitrogen-containingheterocyclyl;

(c) NR¹R² taken together form a substituent selected from substituted orunsubstituted piperidinyl, substituted or unsubstituted piperazinyl,pyrrolinyl, pyrrolidinyl, thiomorpholinyl, and morpholinyl;

(d) NR¹R² taken together form a substituent selected from N—(C₁₋₆alkyl)piperazinyl, N:-phenyl-piperazinyl, 1,3,8-triaza-spiro{4.5}decyl,and 1,4-dioxa-8-aza-spiro{4.5}decyl;

(e) NR¹R² taken together form a monovalent radical of an amine selectedfrom aziridine, 1,4,7-trioxa-10-aza-cyclododecane, thiazolidine,1-phenyl-1,3,8-triaza-spiro{4.5}decan-4-one, piperidine-3-carboxylicacid diethylamide, 1,2,3,4,5,6-hexahydro-{2,3′}bipyridinyl,4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazin-1-yl-pyrimidine,piperidine-4-carboxylic acid amide, methyl-(2-pyridin-2-yl-ethyl)-amine,{2-(3,4-dimethoxy-phenyl)-ethyl}-methyl-amine, thiomorpholinyl,allyl-cyclopentyl-amine, {2-(1H-indol-3-yl)-ethyl}-methyl-amine,1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin-2-yl-amine,phenylamine, pyridin-2-ylamine;

(f) NR¹R² taken together form a substituent selected from the groupconsisting of morpholinyl and piperidinyl, wherein said substituent isoptionally substituted with between 1 and 3 substituents selected fromhydroxy, halo, carboxamide, C₁₋₆ alkyl, C₁₋₆ acyl, 5-9 memberedheterocyclyl, —N(C₁₋₆ alkyl)(5-9 membered heterocyclyl), —NH(5-9membered heterocyclyl), —O(5-9 membered heterocyclyl), (5-9 memberedheterocyclyl)C₁₋₃ alkylene, C₁₋₂-hydroxyalkylene, C₁₋₆ alkoxy, (C₃₋₆cycloalkyl):-O—, phenyl, (phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃alkylene-O— where each of above heterocyclyl, phenyl, and alkyl groupsmay be optionally substituted with from 1 to 3 substituentsindependently selected from trifluoromethyl, halo, nitro, cyano,hydroxy, and C₁₋₃ alkyl;

(g) NR¹R² taken together form a saturated N:-linked nitrogen-containingheterocyclyl substituted with a substituent selected from the groupconsisting of pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl,(imidazolyl)C₁₋₆ alkylene, oxazolyl, thiazolyl, 2,3-dihydro-indolyl,benzimidazolyl, 2-oxobenzimidazolyl, (tetrazolyl)C₁₋₆ alkylene,tetrazolyl, (triazolyl)C₁₋₆ alkylene, triazolyl, (pyrrolyl)C₁₋₆alkylene, pyrrolidinyl, and pyrrolyl;

(h) NR¹R² taken together form morpholinyl, piperidinyl, pyrrolidinyl, ordiethylamino;

(i) NR¹R² taken together form morpholinyl, piperidinyl, or pyrrolidinyl;

(j) NR¹R² taken together form morpholinyl;

(k) one of R³ and R⁴ is G;

(l) R³ is G;

(m) R⁴ is G;

(n) q is 2 and p is 1;

(o) q is 1 and p is 1;

(p) q is 2 and p is 2;

(q) L is —CH₂—;

(r) L is a direct bond;

(s) L is —CH₂CH₂—;

(t) L² is —CH₂—;

(u) Q is selected from substituted or unsubstituted pyrrolidinyl,piperidinyl, methylpiperidinyl, morpholinyl, thiomorpholinyl,azatricyclodecanyl, cyclohexylamino, cyclohexylmethylamino, piperazinyl,N:-methylpiperazinyl, dimethylamino, methylphenethylamino, pyridylamino,anilino, diethylamino, methylethylamino, ethylpropylamino,dipropylamino, or 1,4,7,10-tetraoxa-13-aza-cyclopentadecanyl;

(v) Q is a saturated N:-linked nitrogen-containing heterocyclyl;

(w) Q is selected from substituted or unsubstituted piperidinyl,substituted or unsubstituted piperazinyl, pyrrolinyl, pyrrolidinyl,thiomorpholinyl, and morpholinyl;

(x) substituted Q are selected from N—(C₁₋₆ alkyl)piperazinyl,N:-phenyl-piperazinyl, 1,3,8-triaza-spiro{4.5}decyl, and1,4-dioxa-8-aza-spiro{4.5}decyl;

(y) Q is a monovalent radical of an amine selected from aziridine,1,4,7-trioxa-10-aza-cyclododecane, thiazolidine,1-phenyl-1,3,8-triaza-spiro{4.5}decan-4-one, piperidine-3-carboxylicacid diethylamide, 1,2,3,4,5,6-hexahydro-{2,3′}bipyridinyl,4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazin-1-yl-pyrimidine,piperidine-4-carboxylic acid amide, methyl-(2-pyridin-2-yl-ethyl)-amine,{2-(3,4-dimethoxy-phenyl)-ethyl}-methyl-amine, thiomorpholinyl,allyl-cyclopentyl-amine, {2-(1H-indol-3-yl)-ethyl}-methyl-amine,1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin-2-yl-amine,phenylamine, and pyridin-2-ylamine;

(z) Q is selected from morpholinyl, pyridyl and piperidinyl, optionallysubstituted with between 1 and 3 substituents independently selectedfrom hydroxy, halo, carboxamide, C₁₋₆ alkyl, C₁₋₆ acyl, 5-9 membered or6-9 membered heterocyclyl, —N(C₁₋₆ alkyl)(5-9 membered or 6-9 memberedheterocyclyl), —NH(5-9 membered or 6-9 membered heterocyclyl), —O(5-9 or6-9 membered heterocyclyl), (5-9 membered or 6-9 memberedheterocyclyl)C₁₋₃ alkylene, C₁₋₂-hydroxyalkylene, C₁₋₆ alkoxy, (C₃₋₆cycloalkyl):-O—, phenyl, (phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃alkylene-O— where each of above heterocyclyl, phenyl, and alkyl groupsmay be optionally substituted with from 1 to 3 substituentsindependently selected from trifluoromethyl, halo, nitro, cyano,hydroxy, and C₁₋₃ alkyl;

(aa) Q is substituted with a substituent comprising a 5-9 membered or6-9 membered heterocyclyl group selected from: pyridyl, pyrimidyl,furyl, thiofuryl, imidazolyl, (imidazolyl)C₁₋₆ alkylene, oxazolyl,thiazolyl, 2,3-dihydroindolyl, benzimidazolyl, 2-oxobenzimidazolyl,(tetrazolyl)C₁₋₆ alkylene, tetrazolyl, (triazolyl)C₁₋₆ alkylene,triazolyl, (pyrrolyl)C₁₋₆ alkylene, pyrrolidinyl, and pyrrolyl;

(bb) Q is morpholinyl, piperidinyl, pyrrolidinyl, or diethylamino;

(cc) Q is morpholinyl, piperidinyl, or pyrrolidinyl;

(dd) R⁸ is hydrogen;

(ee) R⁹ is C₁₋₆ alkyl;

(ff) R⁹ is cyclohexyl;

(gg) R⁸ and R⁹ independently are C₁₋₆ alkyl;

(hh) R⁸ and R⁹ are methyl;

(ii) R⁸ and R⁹ are ethyl;

(jj) R⁹ is selected from phenyl or 5-9 membered aromatic heterocyclyl,wherein said phenyl or aromatic heterocyclyl is optionally substitutedwith 1-3 substituents selected from hydroxy, halo, nitro, cyano,trifluoromethyl, and C₁₋₃ alkyl;

(kk) R⁹ is selected from substituted or unsubstituted phenyl, pyridyl,pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C₁₋₆ alkylene,oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl,2-oxobenzimidazolyl, (tetrazolyl)C₁₋₆ alkylene, tetrazolyl,(triazolyl)C₁₋₆ alkylene, triazolyl, (pyrrolyl)C₁₋₁₆ alkylene, andpyrrolyl;

(ll) R⁹ is substituted or unsubstituted phenyl;

(mm) R⁹ is substituted or unsubstituted pyridyl;

(nn) wherein R¹ and R² are independently selected from C₂ alkyl, ortaken together with the nitrogen to which they are attached, they form anon-aromatic 5-6 membered heterocyclyl optionally including anadditional heteroatom independently selected from O, S, and NH; one ofR³, R⁴, and R⁵ is G and the two remaining are H; G is L²Q; L² ismethylene; Q is NR⁸R⁹ wherein R⁸ is independently selected fromhydrogen, C₁₋₂ alkyl, C₃ alkenyl, C₅₋₉ carbocyclyl, 3-12 memberedheterocyclyl (preferably 5-9 or 6-9), phenyl, (5-9-memberedheterocyclyl)C₂ alkylene, and (phenyl)C₂ alkylene; and R⁹ isindependently selected from C₁₋₂ alkyl, C₃ alkenyl, C₅₋₉ carbocyclyl,3-12 membered heterocyclyl (for example, 5-9 membered or 6-9 memberedheterocyclyl, and in some cases preferably 6-membered), phenyl,(5-9-membered heterocyclyl)C₁₋₆ alkylene, and (phenyl)C₁₋₆ alkylene; orQ is a saturated 3-15 membered N:-linked heterocyclyl (preferably 5-9 or6-9), wherein, in addition to the N:-linking nitrogen, the 3-15 memberedheterocyclyl may optionally contain between 1 and 4 additionalheteroatoms independently selected from O, S, and NH; wherein each ofthe above alkyl, alkylene, alkenyl, alkenylene, heterocyclyl,cycloalkyl, and aryl groups may each be independently and optionallysubstituted with substituents selected from tert-butyloxycarbonyl,hydroxy, halo, nitro, amino, cyano, carboxamide, 6-9-memberedheterocyclyl, —NH(6-membered heterocyclyl), —O(6-membered heterocyclyl),C₁₋₂ hydroxyalkylene, C₁₋₂ alkoxy, phenyl, and benzyl, and where each ofabove heterocyclyl, phenyl, and alkyl substituent groups of Q may beoptionally substituted with trifluoromethyl; or a pharmaceuticallyacceptable salt, ester, tautomer, solvate or amide thereof;

(oo) (1) NR¹R² taken together form morpholinyl, piperidinyl,pyrrolidinyl, or diethylamino, and (2) Q is selected from substituted orunsubstituted piperidinyl, piperazinyl, pyrrolinyl, pyrrolidinyl,thiomorpholinyl, and morpholinyl;

(pp) (1) NR¹R² taken together form piperidinyl or pyrrolidinyl, (2) n is1, and (3) Q is selected from morpholinyl and piperidinyl;

(qq) Q is piperidinyl or substituted piperidinyl;

(rr) NR¹R² taken together form piperidinyl, pyrrolidinyl, ordiethylamino, n is 1, and wherein Q is NR⁸R⁹ and R⁸ is H and R⁹ isselected from phenyl or aromatic 5-9 membered heterocyclyl, wherein saidphenyl or heterocyclyl is optionally substituted with 1-3 substituentsselected from trifluoromethyl, halo, nitro, cyano, hydroxy, and C₁₋₃alkyl;

(ss) R^(a) is hydrogen; or

(tt) combinations of (a) through (ss) above.

Examples of compounds of the invention include:

-   4-{2-(4:-Piperidin-1-ylmethyl-piperidin-1-yl)-benzyl}-morpholine;-   Cyclohexyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;-   1-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-azacyclotridecane;-   Diethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;-   Dimethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;-   1-Methyl-4-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperazine;-   1-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidin-4-ol;-   4-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-thiomorpholine;-   1-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;-   4-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;-   4-{3-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-thiomorpholine;-   4-{3-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-morpholine;-   4:-Pyrrolidin-1-ylmethyl-1-(3-pyrrolidin-1-ylmethyl-phenyl)-piperidine;-   1-{3-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine;-   1-{4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-azacyclotridecane;-   Cyclohexyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;-   1-{4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidin-4-ol;-   1-Methyl-4-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperazine;-   4-{4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-thiomorpholine;-   4-{4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-morpholine;-   Dimethyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;-   4-{2-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-morpholine;-   4-{1-(4:-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;-   1-{4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine;-   Cyclohexyl-{1-(4-morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-amine;    Cyclohexyl-methyl-{1-(4-morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-amine;-   4-{4-{4-(4-Methyl-piperazin-1-yl)-piperidin-1-yl}-benzyl}-morpholine;-   Ethyl-methyl-{1-(4-morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-amine;-   4-{1-(4-Morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-morpholine;-   4-{4-(4:-Pyrrolidin-1-yl-piperidin-1-yl)-benzyl}-morpholine;-   1′-(4-Morpholin-4-ylmethyl-phenyl)-{1,4′}bipiperidinyl;-   1′-(4:-Piperidin-1-ylmethyl-phenyl)-{1,4′}bipiperidinyl;-   (4-{1,4′}Bipiperidinyl-1′-yl-benzyl)-pyridin-2-yl-amine;-   Phenyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;-   Pyridin-2-yl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;-   1-{1-(4:-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;-   4:-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine;-   (4:-Fluoro-phenyl)-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;-   4-{2-{1-(4:-Piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-morpholine;-   Diethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;-   Methyl-phenethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;-   1-[4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-3-trifluoromethyl-benzyl]-piperidine;-   1-(2:-Nitro-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-piperidine;-   4-[3:-Nitro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-morpholine;-   1-[3:-Nitro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidin-4-ol;-   1-[4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-2-trifluoromethyl-benzyl]-piperidine;-   1:-Isopropyl-4-[3-methyl-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperazine;-   1-(2-Methyl-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidine;-   1-[3-Methyl-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-pyrrolidine;-   1-{1-[4-(4:-Pyrrolidin-1-yl-piperidin-1-ylmethyl)-2-trifluoromethyl-phenyl]-piperidin-4-ylmethyl}-pyrrolidine;-   1-(1-{3-Trifluoromethyl-4-[4-(4-trifluoromethyl-phenyl)-piperidin-1-ylmethyl]-phenyl}-piperidin-4-ylmethyl)-pyrrolidine;-   1-{1-[2:-Fluoro-4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-piperidin-4-ylmethyl}-pyrrolidine;-   [3:-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-dimethyl-amine;-   1-[3:-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidine;-   13-[4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-2-trifluoromethyl-benzyl]-1,4,7,10-tetraoxa-13-aza-cyclopentadecane    ditrifluoromethanesulfonate; and-   {1-[4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-3-trifluoromethyl-benzyl]-piperidin-4-yl}-methanol.

Preferred example compounds include:

-   (4-{1,4′}Bipiperidinyl-1′-yl-benzyl)-pyridin-2-yl-amine;-   1′-(4-Morpholin-4-ylmethyl-phenyl)-{1,4′}bipiperidinyl;-   1′-(4:-Piperidin-1-ylmethyl-phenyl)-{1,4′}bipiperidinyl;-   1-{1-(4:-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;-   4-{1-(4:-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;-   1-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidin-4-ol;-   1-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;-   1-{3-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine;-   1-{4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-azacyclotridecane;-   1-{4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidin-4-ol;-   1-{4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine;-   1-Methyl-4-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperazine;-   1-Methyl-4-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperazine;-   4-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;-   4-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-thiomorpholine;-   4-{3-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-thiomorpholine;-   4-{4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-thiomorpholine;-   4-{2-{1-(4:-Piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-morpholine;-   4:-Pyrrolidin-1-ylmethyl-1-(3-pyrrolidin-1-ylmethyl-phenyl)-piperidine;-   4:-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine;-   Cyclohexyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;-   Cyclohexyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;-   Cyclohexyl-methyl-{1-(4-morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-amine;-   Diethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;-   Diethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;-   Dimethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;-   Dimethyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;-   Methyl-phenethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;-   Phenyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;-   Pyridin-2-yl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;-   1-(2:-Nitro-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-piperidine;-   1-[3:-Nitro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidin-4-ol;-   1-[4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-2-trifluoromethyl-benzyl]-piperidine;-   1-(2-Methyl-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidine;-   1-[3-Methyl-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-pyrrolidine;-   1-{1-[4-(4:-Pyrrolidin-1-yl-piperidin-1-ylmethyl)-2-trifluoromethyl-phenyl]-piperidin-4-ylmethyl}-pyrrolidine;-   1-{1-[2:-Fluoro-4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-piperidin-4-ylmethyl}-pyrrolidine;-   [3:-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-dimethyl-amine;    and-   1-[3:-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidine.

More preferred example compounds include:

-   1′-(4:-Piperidin-1-ylmethyl-phenyl)-{1,4′}bipiperidinyl;-   1-{1-(4:-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;-   4-{1-(4:-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;-   1-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidin-4-ol;-   1-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;-   1-{4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidin-4-ol;-   1-{4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine;-   1-Methyl-4-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperazine;-   4-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;-   4-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-thiomorpholine;-   4-{4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-thiomorpholine;-   4-{2-{1-(4:-Piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-morpholine;-   4:-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine;-   Cyclohexyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;-   Cyclohexyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;-   Diethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;-   Diethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;-   Dimethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;-   Dimethyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;-   Methyl-phenethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;-   Pyridin-2-yl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;-   1-(2:-Nitro-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-piperidine;-   1-[3:-Nitro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidin-4-ol;-   1-(2-Methyl-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidine;-   [3:-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-dimethyl-amine;    and-   1-[3:-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidine.

Even more preferred example compounds include:

-   1-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidin-4-ol;-   1-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;-   1-Methyl-4-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperazine;-   1-{4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine;-   4-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine;-   4-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-thiomorpholine;-   4-{2-{1-(4:-Piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-morpholine;-   4:-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine;-   Cyclohexyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;-   Cyclohexyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine;-   Diethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;-   Diethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;-   Dimethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;-   Methyl-phenethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;-   1-(2:-Nitro-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-piperidine;    and-   1-(2-Methyl-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidine.

Yet even more preferred example compounds include:

-   1-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidin-4-ol;-   1-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine;-   4:-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine;-   4-{2-{1-(4:-Piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-morpholine;-   Cyclohexyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;-   Diethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;-   Diethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;    and-   1-(2-Methyl-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidine.

The invention also provides compounds that are useful as syntheticintermediates of the compounds of the invention. Such compounds, whichthemselves may or may not have pharmaceutical activity, include thoseprovided in the schemes and synthetic examples.

The invention also contemplates compounds isotopicallylabelled to bedetectable by positron emission tomography (PET) or single-photonemission computed tomography (SPECT) useful for studying H₃-mediateddisorders.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. Inaddition, compounds of the invention may be modified by using protectinggroups; such compounds, precursors, or prodrugs are also within thescope of the invention. This may be achieved by means of conventionalprotecting groups, such as those described in “Protective Groups inOrganic Chemistry”, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 3^(rd)ed., John Wiley & Sons, 1999. The protecting groups may be removed at aconvenient subsequent stage using methods known from the art.

Hydroxyl Protecting Groups

Protection for the hydroxyl group includes methyl ethers, substitutedmethyl ethers, substituted ethyl ethers, substitute benzyl ethers, andsilyl ethers.

Substituted Methyl Ethers

Examples of substituted methyl ethers include methyoxymethyl,methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl,benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl,guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxido, 1-{(2-chloro-4-methyl)phenyl}-4-methoxypiperidin-4-yl,1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.

Substituted Ethyl Ethers

Examples of substituted ethyl ethers include 1-ethoxyethyl,1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, andbenzyl.

Substituted Benzyl Ethers

Examples of substituted benzyl ethers include p-methoxybenzyl,3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl,3-methyl-2-picolyl N:-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl,5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(Imidazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.

Silyl Ethers

Examples of silyl ethers include trimethylsilyl, triethylsilyl,triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl,dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl,and t-butylmethoxyphenylsilyl.

Esters

In addition to ethers, a hydroxyl group may be protected as an ester.Examples of esters include formate, benzoylformate, acetate,chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, phenoxyacetate,p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate,4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate(mesitoate)

Carbonates

Examples of carbonates include methyl, 9-fluorenylmethyl, ethyl,2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl,2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl,benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, and methyldithiocarbonate.

Assisted Cleavage

Examples of assisted cleavage include 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate,4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.

Miscellaneous Esters

Examples of miscellaneous esters include2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),o-(methoxycarbonyl)benzoate, p-P-benzoate, o-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, N:-phenylcarbamate, borate,dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate

Sulfonates

Examples of sulfonates include sulfate, methanesulfonate(mesylate),benzylsulfonate, and tosylate.

Protection for 1,2- and 1,3-Diols

Cyclic Acetals and Ketals

Examples of cyclic acetals and ketals include methylene, ethylidene,1-t-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl)ethylidene,2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene,cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene,2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and2-nitrobenzylidene.

Cyclic Ortho Esters

Examples of cyclic ortho esters include methoxymethylene,ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene,1-ethoxyethylidine, 1,2-dimethoxyethylidene, α-methoxybenzylidene,1-(N,N:-dimethylamino)ethylidene derivative,α-(N,N:-dimethylamino)benzylidene derivative, and 2-oxacyclopentylidene.

Silyl Derivatives

Examples of silyl derivatives include di-t-butylsilylene group, and1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative.

Amino Protecting Groups

Protection for the amino group includes carbamates, amides, and special—NH protective groups.

Examples of carbamates include methyl and ethyl carbamates, substitutedethyl carbamates, assisted cleavage carbamates, photolytic cleavagecarbamates, urea-type derivatives, and miscellaneous carbamates.

Carbamates

Examples of methyl and ethyl carbamates include methyl and ethyl,9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl,9-(2,7-dibromo)fluorenylmethyl,2,7-di-t-butyl-{9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)}methyl,and 4-methoxyphenacyl.

Substituted Ethyl

Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl,2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl,1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2′- and 4′-pyridyl)ethyl,2-(N,N:-dicyclohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl,allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl,N:-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl,p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl,4-methylsulfinylbenzyl, 9-anthrylmethyl and diphenylmethyl.

Assisted Cleavage

Examples of assisted cleavage include 2-methylthioethyl,2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,{2-(1,3-dithianyl)}methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl,2-phosphonioethyl, 2-triphenylphosphonioisopropyl,1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl,p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, and2-(trifluoromethyl)-6-chromonylmethyl.

Photolytic Cleavage

Examples of photolytic cleavage include m-nitrophenyl,3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, andphenyl(o-nitrophenyl)methyl.

Urea-Type Derivatives

Examples of urea-type derivatives include phenothiazinyl-(10)-carbonylderivative, N′-p-toluenesulfonylaminocarbonyl, andN′-phenylaminothiocarbonyl.

Miscellaneous Carbamates

Examples of miscellaneous carbamates include t-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl,2,2-dimethoxycarbonylvinyl, o-(N,N:-dimethylcarboxamido)benzyl,1,1-dimethyl-3-(N,N:-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl,di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl,isonicotinyl, p-(p′-methoxyphenylazo)benzyl, 1-methylcyclobutyl,1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,1-methyl-1-(3,5-dimethoxyphenyl)ethyl,1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl, and2,4,6-trimethylbenzyl.

Examples of Amides Include:

Amides

N:-formyl, N:-acetyl, N:-chloroacetyl, N:-trichloroacetyl,N:-trifluoroacetyl, N:-phenylacetyl, N-3-phenylpropionyl, N:-picolinoyl,N-3-pyridylcarboxamide, N:-benzoylphenylalanyl derivative, N:-benzoyl,N-p-phenylbenzoyl.

Assisted Cleavage

N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N:-acetoacetyl,(N′-dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl,N-3-(o-nitrophenyl)propionyl, N2-methyl-2-(o-nitrophenoxy)propionyl,N2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N:-acetylmethioninederivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and4,5-diphenyl-3-oxazolin-2-one.

Cyclic Imide Derivatives

N:-phthalimide, N:-dithiasuccinoyl, N-2,3-diphenylmaleoyl,N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentaneadduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and1-substituted 3,5-dinitro-4-pyridonyl.

Special—NH Protective Groups

Examples of special NH protective groups include:

N-Alkyl and N-Aryl Amines

N:-methyl, N:-allyl, N-{2-(trimethylsilyl)ethoxy}methyl,N-3-acetoxypropyl, N:-(1:-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl),quaternary ammonium salts, N:-benzyl, N-4-methoxybenzyl,N:-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N:-triphenylmethyl,N:-(4:-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,N-2,7-dichloro-9-fluorenylmethylene, N:-ferrocenyl methyl, andN2-picolylamine N′-oxide.

Imine Derivatives

N-1,1-dimethylthiomethylene, N:-benzylidene, N-p-methoxybenzylidene,N:-diphenylmethylene, N-{(2-pyridyl)mesityl}methylene, andN—(N′,N′-dimethylaminomethylene).

Protection for the Carbonyl Group

Acyclic Acetals and Ketals

Examples of acyclic acetals and ketals include dimethyl,bis(2,2,2-trichloroethyl), dibenzyl, bis(2-nitrobenzyl) and diacetyl.

Cyclic Acetals and Ketals

Examples of cyclic acetals and ketals include 1,3-dioxanes,5-methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane,5-(2-pyridyl)-1,3-dioxane, 1,3-dioxolanes, 4-bromomethyl-1,3-dioxolane,4-(3-butenyl)-1,3-dioxolane, 4-phenyl-1,3-dioxolane,4-(2-nitrophenyl)-1,3-dioxolane, 4,5-dimethoxymethyl-1,3-dioxolane,O,O′-phenylenedioxy and 1,5-dihydro-3H:-2,4-benzodioxepin.

Acyclic Dithio Acetals and Ketals

Examples of acyclic dithio acetals and ketals include S,S′-dimethyl,S,S′-diethyl, S,S′-dipropyl, S,S′-dibutyl, S,S′-dipentyl, S,S′-diphenyl,S,S′-dibenzyl and S,S′-diacetyl.

Cyclic Dithio Acetals and Ketals

Examples of cyclic dithio acetals and ketals include 1,3-dithiane,1,3-dithiolane and 1,5-dihydro-3H:-2,4-benzodithiepin.

Acyclic Monothio Acetals and Ketals

Examples of acyclic monothio acetals and ketals includeO-trimethylsilyl-S-alkyl, O-methyl-5-alkyl or —S-phenyl andO-methyl-S-2-(methylthio)ethyl.

Cyclic Monothio Acetals and Ketals

Examples of cyclic monothio acetals and ketals include 1,3-oxathiolanes.

Miscellaneous Derivatives

O:-Substituted Cyanohydrins

Examples of O-substituted cyanohydrins include O-acetyl,O-trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.

Substituted Hydrazones

Examples of substituted hydrazones include N,N:-dimethyl and2,4-dinitrophenyl.

Oxime Derivatives

Examples of oxime derivatives include O-methyl, O-benzyl andO-phenylthiomethyl.

Imines

Substituted Methylene Derivatives, Cyclic Derivatives

Examples of substituted methylene and cyclic derivatives includeoxazolidines, 1-methyl-2-(1′-hydroxyalkyl)imidazoles,N,N′-dimethylimidazolidines, 2,3-dihydro-1,3-benzothiazoles,diethylamine adducts, and methylaluminumbis(2,6-di-t-butyl-4-methylphenoxide)(MAD)complex.

Monoprotection of Dicarbonyl Compounds

Selective Protection Of α- and β-Diketones

Examples of selective protection of α- and β-diketones include enamines,enol acetates, enol ethers, methyl, ethyl, i-butyl, piperidinyl,morpholinyl, 4-methyl-1,3-dioxolanyl, pyrrolidinyl, benzyl, S-butyl, andtrimethylsilyl.

Cyclic Ketals, Monothio and Dithio Ketals Examples of cyclic ketals,monothio and dithio ketals include bismethylenedioxy derivatives andtetramethylbismethylenedioxy derivatives.

Protection for the Carboxyl Group

Esters

Substituted Methyl Esters

Examples of substituted methyl esters include 9-fluorenylmethyl,methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl,methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl,phenacyl, p-bromophenacyl, α-methylphenacyl, p-methoxyphenacyl,carboxamidomethyl, and N:-phthalimidomethyl.

2:-Substituted Ethyl Esters

Examples of 2-substituted ethyl esters include 2,2,2-trichloroethyl,

2-haloethyl, ω-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl,1,3-dithianyl-2-methyl, 2-(p-nitrophenylsulfenyl)ethyl,2-(p-toluenesulfonyl)ethyl,

2-(2′-pyridyl)ethyl, 2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl,t-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl,4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, α-methylcinnamyl, phenyl,p-(methylmercapto)phenyl and benzyl.

Substituted Benzyl Esters

Examples of substituted benzyl esters include triphenylmethyl,diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl,2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl,2-(trifluoromethyl)-6-chromylmethyl, 2,4,6-trimethylbenzyl,p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl,2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl,4-picolyl and p-P-benzyl.

Silyl Esters

Examples of silyl esters include trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, i-propyldimethylsilyl, phenyldimethylsilyl anddi-t-butylmethylsilyl.

Activated Esters

Examples of activated esters include thiols.

Miscellaneous Derivatives

Examples of miscellaneous derivatives include oxazoles,2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines,5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group andpentaminocobalt (III) complex.

Stannyl Esters

Examples of stannyl esters include triethylstannyl andtri-n-butylstannyl.

Amides and Hydrazides

Amides

Examples of amides include N,N:-dimethyl, pyrrolidinyl, piperidinyl,5,6-dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl,N-8:-Nitro-1,2,3,4-tetrahydroquinolyl, and p-P-benzenesulfonamides.

Hydrazides

Examples of hydrazides include N:-phenyl and N,N′-diisopropyl.

The compounds of the invention can be prepared according to the methodsdescribed in the next section.

C. SYNTHESIS

The compounds of the invention can be prepared according to traditionalsynthetic organic methods and matrix or combinatorial chemistry methods,as shown in Schemes 1-7 below and in Examples 1-82. A person of ordinaryskill will be aware of variations and adaptations of the schemes andexamples provided to achieve the compounds of the invention.

One skilled in the art will recognize that synthesis of the compounds ofthe present invention may be effected by purchasing intermediate orprotected intermediate compounds described in any of the schemesdisclosed herein. Throughout the schemes when the reacting functionalityis located at R³, one skilled in the art will recognize that the choiceof R³ is illustrative only and that the reacting functionality couldalso be located at R⁴ or R⁵.

One skilled in the art will further recognize that during any of theprocesses for preparation of the compounds of the present invention, itmay be necessary and/or desirable to protect sensitive or reactivegroups on any of the molecules concerned. This may be achieved by meansof conventional protecting groups, such as those described in“Protective Groups in Organic Chemistry”, ed. J. F. W. McOmie, PlenumPress, 1973; and T. W. Greene & P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, John Wiley & Sons, 1991. The protecting groups maybe removed at a convenient subsequent stage using methods known from theart.

Compounds of formula (VIII) may be prepared according to the processesoutlined in Scheme 1.

A compound of formula (VIII) is prepared as outlined in Scheme 1 from acompound of formula (IV). A compound of formula (IV) is reacted with areagent capable of introducing a nitrogen-protecting group M¹ undernitrogen-protection conditions. In a particularly preferred embodiment,a compound of formula (IV) is reacted with di-tert-butyl dicarbonate inDCM at room temperature. A compound of formula (VI) is obtained from acompound of formula (V) by reacting a compound of formula (V) with anoxidizing agent in a solvent at room temperature under alcohol oxidizingconditions. In a preferred embodiment, a compound of formula (V) isreacted with 4-methylmorpholine N:-oxide and tetrapropylammoniumperruthenate in the presence of a dehydrating agent such as 4 Amolecular sieves in a solvent such as DCE or DCM. A compound of formula(VII) is obtained from a compound of formula (VI) by reacting a compoundof formula (VI) with a compound of formula (XXX) under reductiveamination conditions in the presence of a reductant such as sodiumtriacetoxyborohydride, sodium cyanoborohydride, or phenylsilane in asolvent such as THF, DCE, DCM, methanol, ethanol, or ether at atemperature between 0 and 80° C. One skilled in the art will recognizethat the use of a promotor or catalyst with acidic character such asorganometallic complexes or carboxylic acids may increase the rate ofthe reaction and/or reduce the formation of by-products. In aparticularly preferred embodiment, a compound of formula (VI) is reactedwith a compound of formula (XXX), acetic acid, and sodiumtriacetoxyborohydride in DCE at room temperature. A compound of formula(VIII) is obtained from a compound of formula (VII) by reacting acompound of formula (VII) with a reagent capable of removing theprotecting group M¹ under nitrogen deprotection conditions. In apreferred embodiment a compound of formula (VII), in which theprotecting group M¹ is tert-butyl carbamoyl, is reacted with an acidsuch as anhydrous hydrogen chloride in a solvent such as dioxane at roomtemperature.

Compounds of formula (XIII) may be prepared according to the processesoutlined in Scheme 2.

A compound of formula (XIII) is prepared as outlined in Scheme 2 from acompound of formula (IX). A compound of formula (IX) is reacted with areagent capable of converting a compound of formula (IX) to a compoundof formula (X), in which M² represents a nitrogen-protecting group,under nitrogen-protecting conditions. In a preferred embodiment, theprotecting group M² is benzyl and is introduced by reacting a compoundof formula (IX) with benzaldehyde under reductive amination conditionsas outlined in Scheme 1, step C. A compound of formula (XI) is obtainedfrom a compound of formula (X) by reacting a compound of formula (X)with an acid in a solvent at a temperature from 0 to 100° C. under ketalhydrolysis conditions. In a particularly preferred embodiment, acompound of formula (X) is reacted with hydrochloric acid in water at100° C. A compound of formula (XII) is obtained from a compound offormula (XI) by reacting a compound of formula (XI) with a compound offormula (XXX) under reductive amination conditions, as described inScheme 1, step C. A compound of formula (XIII) is obtained from acompound of formula (XII) by reacting a compound of formula (XII) with areagent capable of removing the protecting group M². In a preferredembodiment, a compound of formula (XII), in which M² represents thebenzyl group, is reacted with a reducing agent such as hydrogen gas inthe presence of a hydrogenation catalyst such as palladium on carbon atroom temperature.

Compounds of formula (XVII) or formula (XX) may be prepared as outlinedaccording to the processes outlined in Scheme 3.

A compound of formula (XVII) or formula (XX) is prepared as outlined inScheme 3 from a compound of formula (XIV). A compound of formula (XVI)is prepared from a compound of formula (XIV) by reacting a compound offormula (XIV) with a compound of formula (XV) under nucleophilic,aromatic substitution conditions. In a preferred embodiment, a compoundof formula (XIV) is reacted with a compound of formula (XV) in thepresence of a base such as sodium carbonate, potassium carbonate, cesiumcarbonate, sodium hydride, or tetramethylguanidine in a solvent such asDMF, DMAC, THF, DME, DCM, or ether at a temperature between 0 and 150°C. In a particularly preferred embodiment, a compound of formula (XIV)is reacted with a compound of formula (XV) in the presence of cesiumcarbonate or potassium carbonate in DMF at 100° C. A compound of formula(XVII) is prepared by reacting a compound of formula (XVI) with acompound of formula (XXXI) under reductive amination conditions, asdescribed in Scheme 1, step C. A compound of formula (XIX) is obtainedfrom a compound of formula (XIV) by reacting a compound of formula (XIV)with a compound of formula (XVIII) under amine N:-arylation conditions.In a preferred embodiment, a compound of formula (XIV) is reacted with acompound of formula (XVIII) in the presence of a metal complex such ascopper(II) acetate, a base such as triethylamine or 2,6-lutidine in thepresence of an air atmosphere in a solvent such as toluene or DCM. Oneskilled in the art will recognize that the addition of a carboxylic acidsuch as myristic acid and/or a drying agent such as 4 A molecular sievesmay improve the yield of the reaction and/or reduce by-productformation. In a particularly preferred embodiment, the metal complex iscopper(III) acetate, the base is triethylamine, the solvent is DCM, andthe reaction is performed in the presence of 4 A molecular sieves. Acompound of formula (XX) is prepared by reacting a compound of formula(XIX) with a compound of formula (XXXI) under reductive aminationconditions, as described in Scheme 1, step C.

Compounds of formula (XXIV) may be prepared according to the processesoutlined in Scheme 4.

A compound of formula (XXIV) is prepared as outlined in Scheme 4 from acompound of formula (IV). A compound of formula (IV) is reacted with acompound of formula (XV) under nucleophilic aromatic substitutionconditions, as described in Scheme 3, step A. A compound of formula(XXI) is reacted with a compound of formula (XXXI) under reductiveamination conditions, as described in Scheme 1, step C. A compound offormula (XXIII) is prepared from a compound of formula (XXII) byreacting a compound of formula (XXII) with an oxidizing agent underalcohol oxidizing conditions. In a preferred embodiment, a compound offormula (XXII) is reacted with an oxidant such as DMSO in combinationwith oxalyl chloride in the presence of an organic base such astriethylamine in a solvent such as DCM at a temperature from −78° C. toroom temperature. A compound of formula (XXIV) is obtained by reacting acompound of formula (XXIII) with a compound of formula (XXX) underreductive amination conditions, as described in Scheme 1, step C.

Compounds of formula (XXVI) may be prepared according to the processesoutlined in Scheme 5.

A compound of formula (XXVI) is prepared from a compound of formula(XXI) as shown in Scheme 5. A compound of formula (XXV) is prepared byreacting a compound of formula (XXI) under alcohol oxidation conditionsas described in Scheme 4, step C. A compound of formula (XXVI) isprepared by reacting a compound of formula (XXV) with a compound offormula (XXX) under reductive amination conditions as described inScheme 1, step C.

Compounds of formula (XXXIII) may be prepared according to the processesoutlined in Scheme 6.

A compound of formula (XXXIII) is prepared as outlined in Scheme 6 froma compound of formula (IX). A compound of formula (XXVII) is preparedfrom a compound of formula (IX) by reacting a compound of formula (IX)with a compound of formula (XV) under nucleophilic, aromaticsubstitution conditions as described in Scheme 3, step A. A compound offormula (XXVIII) is prepared from a compound of formula (XXVII) byreacting a compound formula (XXVII) with a compound of formula (XXXI)under reductive amination conditions as described in Scheme 1, step C. Acompound of formula (XXIX) is prepared from a compound of formula(XXVIII) by reacting a compound of formula (XXVIII) under ketalhydrolysis conditions as outlined in Scheme 2, step B. A compound offormula (XXXIII) is prepared by reacting a compound of formula (XXIX)with a compound of formula (XXX) under reductive amination conditions asdescribed in Scheme 1, step C.

Compounds of formula (XXXIV) may be prepared according to the processesoutlined in Scheme 7.

A compound of formula (XXXIV) is prepared from a compound of formula(XXII) as shown in Scheme 7. A compound of formula (XXXIV) is preparedby reacting a compound of formula (XXII) with a compound of formula(XXX) under rearranging, nucleophilic substitution conditions. In apreferred embodiment, a compound of formula (XXII) is reacted with acompound of formula (XXX) in the presence of a reagent capable ofconverting the hydroxyl functionality to a leaving group such astrimethylcyanomethylphosphonium iodide and a base such asN:-ethyl:-N,N:-diisopropylamine in a solvent such as acetonitrile orpropionitrile at a temperature from 0° C. to 100° C. In a particularlypreferred embodiment, a compound of formula (XXII) is reacted with acompound of formula (XXX) in the presence oftrimethylcyanomethylphosphonium iodide andN:-ethyl:-N,N:-diisopropylamine in propionitrile at 90° C.

D. FORMULATION, ADMINISTRATION, AND THERAPY

The disclosed compounds, alone or in combination (with, for example, ahistamine H₁ receptor antagonist), are useful for treating or preventingneurologic disorders including sleep/wake and arousal/vigilancedisorders (e.g. insomnia and jet lag), attention deficit hyperactivitydisorders (ADHD), learning and memory disorders, cognitive dysfunction,migraine, neurogenic inflammation, dementia, mild cognitive impairment(pre-dementia), Alzheimer's disease, epilepsy, narcolepsy, eatingdisorders, obesity, motion sickness, vertigo, schizophrenia, substanceabuse, bipolar disorders, manic disorders and depression, as well asother histamine H₃ receptor mediated disorders such as upper airwayallergic response, asthma, itch, nasal congestion and allergic rhinitisin a subject in need thereof.

1. Formulation and Administration

The compounds or compositions of the invention may be formulated andadministered to a subject by any conventional route of administration,including, but not limited to, intravenous, oral, subcutaneous,intramuscular, intradermal and parenteral administration. The quantityof the compound that is effective for treating each condition may vary,and can be determined by one of ordinary skill in the art.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts that may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts.

Thus, representative pharmaceutically acceptable salts include thefollowing: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N:-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds that are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound that may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985. Inaddition to salts, the invention provides the esters, amides, and otherprotected or derivatized forms of the described compounds.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

The present invention also provides pharmaceutical compositionscomprising one or more compounds of this invention in association with apharmaceutically acceptable carrier and optionally additionalpharmaceutical agents such as H₁ antagonists or SSRIs. Preferably thesecompositions are in unit dosage forms such as pills, tablets, caplets,capsules (each including immediate release, timed release and sustainedrelease formulations), powders, granules, sterile parenteral solutionsor suspensions (including syrups and emulsions), metered aerosol orliquid sprays, drops, ampoules, autoinjector devices or suppositories;for oral, parenteral, intranasal, sublingual or rectal administration,or for administration by inhalation or insufflation. Alternatively, thecomposition may be presented in a form suitable for once-weekly oronce-monthly administration; for example, an insoluble salt of theactive compound, such as the decanoate salt, may be adapted to provide adepot preparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid pre-formulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these pre-formulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid pre-formulation composition is then subdivided into unit dosageforms of the type described above containing from 5 to about 1000 mg ofthe active ingredient of the present invention. Examples include 5 mg, 7mg, 10 mg, 15 mg, 20 mg, 35 mg, 50 mg, 75 mg, 100 mg, 120 mg, 150 mg,and so on. The tablets or pills of the disclosed compositions can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer, which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of material can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography.

The compounds may be prepared in racemic form, or individual enantiomersmay be prepared either by enantiospecific synthesis or by resolution.The compounds may, for example, be resolved into their componentenantiomers by standard techniques, such as the formation ofdiastereomeric pairs by salt formation with an optically active acid,such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-I-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The compound of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phophatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment is required.

The daily dosage of the products may be varied over a wide range from 1to 1,000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing1.0, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thesubject to be treated. An effective amount of the drug is ordinarilysupplied at a dosage level of from about 0.01 mg/kg to about 20 mg/kg ofbody weight per day. Preferably, the range is from about 0.02 mg/kg toabout 10 mg/kg of body weight per day, and especially from about 0.05mg/kg to about 10 mg/kg of body weight per day. The compounds may beadministered on a regimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

2. Combination Therapy

The disclosed compounds are useful in combination with other therapeuticagents, including H₁ receptor antagonists, H₂ receptor antagonists, andneurotransmitter modulators such as SSRIs and non-selective serotoninre-uptake inhibitors (NSSRIs).

Methods are known in the art for determining effective doses fortherapeutic and prophylactic purposes for the disclosed pharmaceuticalcompositions or the disclosed drug combinations, whether or notformulated in the same composition. For therapeutic purposes, the term“jointly effective amount” as used herein, means that amount of eachactive compound or pharmaceutical agent, alone or in combination, thatelicits the biological or medicinal response in a tissue system, animalor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes alleviation of the symptoms ofthe disease or disorder being treated. For prophylactic purposes (i.e.,inhibiting the onset or progression of a disorder), the term “jointlyeffective amount” refers to that amount of each active compound orpharmaceutical agent, alone or in combination, that inhibits in asubject the onset or progression of a disorder as being sought by aresearcher, veterinarian, medical doctor or other clinician, thedelaying of which disorder is mediated, at least in part, by themodulation of one or more histamine receptors. Thus, the presentinvention provides combinations of two or more drugs wherein, forexample, (a) each drug is administered in an independentlytherapeutically or prophylactically effective amount; (b) at least onedrug in the combination is administered in an amount that issub-therapeutic or sub-prophylactic if administered alone, but istherapeutic or prophylactic when administered in combination with thesecond or additional drugs according to the invention; or (c) both drugsare administered in an amount that is sub-therapeutic orsub-prophylactic if administered alone, but are therapeutic orprophylactic when administered together. Combinations of three or moredrugs are analogously possible. Methods of combination therapy includeco-administration of a single formulation containing all active agents;essentially contemporaneous administration of more than one formulation;and administration of two or more active agents separately formulated.

E. EXAMPLES

In order to illustrate the invention, the following examples areincluded. These examples do not limit the invention. They are only meantto suggest a method of practicing the invention. Those skilled in theart may find other methods of practicing the invention, which areobvious to them. However, those methods are deemed to be within thescope of this invention.

Protocol for Preparative Reversed-Phase HPLC

Gilson®

Column: YMC:-Pack ODS-A, 5 μm, 75×30 mm

Flow rate: 25 mL/min

Detection: λ=220 & 254 nm

Gradient (acetonitrile/water, 0.05% trifluoroacetic acid) 1)  0.0 min15% acetonitrile/85% water 2) 20.0 min 99% acetonitrile/1% water

Protocol for HPLC (Reversed-Phase)

Hewlett Packard Series 1100

Column: Agilent ZORBAX® Bonus RP, 5 μm, 4.6×250 mm

Flow rate: 1 mL/min

Detection: λ=220 & 254 nm

Gradient (acetonitrile/water, 0.05% trifluoroacetic acid) 1)  0.0 min 1% acetonitrile/99% water 2) 20.0 min 99% acetonitrile/1% water

Mass spectra were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in either positive or negative modes asindicated.

Thin-layer chromatography was performed using Merck silica gel 60 F₂₅₄2.5 cm×7.5 cm 250 μm or 5.0 cm×10.0 cm 250 μm pre-coated silica gelplates. Preparative thin-layer chromatography was performed using EMScience silica gel 60 F₂₅₄ 20 cm×20 cm 0.5 mm pre-coated plates with a20 cm×4 cm concentrating zone.

NMR spectra were obtained on either a Bruker model DPX400 (400 MHz) orDPX500 (500 MHz) spectrometer. The format of the ¹H NMR data below is:chemical shift in ppm down field of the tetramethylsilane reference(multiplicity, coupling constant J in Hz, integration).

Example 1

4:-Hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester

To a solution of 4-piperidinemethanol (37.2 g) in dichloromethane (DCM,300 mL) was added di-tert-butyl dicarbonate (70.5 g) in severalportions. The resulting mixture was stirred at room temperatureovernight. The reaction mixture was diluted with DCM (700 mL), andwashed with water (200 mL), saturated ammonium chloride (200 mL) andbrine (200 mL). The combined extracts were dried (MgSO₄) andconcentrated under reduced pressure, giving the title compound as awhite solid (69.5 g).

Example 2

4:-Formyl-piperidine-1-carboxylic acid tert-butyl ester

To a mixture of the product of Example 1 (23.1 g), 4-methylmorpholineN:-oxide (NMO, 18.9 g) and 4 A molecular sieves (53.5 g) in DCM (214 mL)was added tetrapropylammonium perruthenate (TPAP, 1.9 g) portion-wise atroom temperature. The reaction mixture was stirred at room temperaturefor 1 h and filtered through a pad of silica gel. Evaporation of solventgave the title compound as a light yellow oil (15.0 g).

Example 3

4:-Pyrrolidin-1-ylmethyl-piperidine-1-carboxylic acid tert-butyl ester

To a solution of the product of Example 2 (2.0 g) in DCM (40 mL) wasadded pyrrolidine (1.0 g) followed by sodium triacetoxyborohydride (2.8g). The resulting mixture was stirred overnight, and treated with 10%NaOH (20 mL). The resulting mixture was extracted with DCM (300 mL). Thecombined extracts were washed with water (50 mL) and brine (50 mL),dried (MgSO₄), and concentrated under reduced pressure to give the titlecompound as a light pink-brown oil (2.4 g).

Example 4

4:-Pyrrolidin-1-ylmethyl-piperidine

To a solution of the product of Example 3 (2.4 g) in dioxane (30 mL) wasadded 4 N HCl in dioxane (30 mL). The resulting mixture was stirred atroom temperature overnight, concentrated, and treated with 10% NaOH (50mL). The resulting mixture was extracted with DCM (2×100 mL). Thecombined extracts were washed with water (30 mL) and brine (30 mL), andconcentrated under reduced pressure to give the title compound as abrown-yellow oil (0.81 g).

Example 5

4-{1,4′}Bipiperidinyl-1′-yl-benzaldehyde

A mixture of 4-fluorobenzaldehyde (1 mL), {1,4′}bipiperidinyl (829.6mg), and potassium carbonate (0.72 g) in DMF (3 mL) was heated to 100°C. for 6 h. The cooled reaction mixture was poured into water (200 mL)and then extracted with DCM. Removal of the solvent and chromatographyof the residue on silica gel (1-7% 2 M methanolic ammonia/DCM) gave thetitle compound (838.3 mg).

Example 6

4-(4:-Hydroxymethyl-piperidin-1-yl)-benzaldehyde

A suspension of 4-fluorobenzaldehyde (4.3 mL), 4-hydroxymethylpiperidine(4.8 g), and cesium carbonate (26 g) in DMF (80 mL) was heated to 100°C. for 24 h and cooled to room temperature. Water (400 mL) was added,and the resulting precipitate was collected by filtration to give thetitle compound as a tan amorphous powder (4.1 g).

The compounds of Example 7 through Example 9 were prepared according tothe procedure of Example 6 from the specified fluorobenzaldehde andsecondary amine.

Example 7

2-(4:-Hydroxymethyl-piperidin-1-yl)-benzaldehyde

Prepared from 2-fluorobenzaldehyde and 4-hydroxymethylpiperidine.

Example 8

4-(1,4-Dioxa-8-aza-spiro{4.5}dec-8-yl)-benzaldehyde

Prepared from 4-fluorobenzaldehyde and 1,4-dioxa-8-aza-spiro{4.5}decane.

Example 9

4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzaldehyde

Prepared from 4-fluorobenzaldehyde and the product of Example 4.

Example 10

{1-(4:-Piperidin-1-ylmethyl-phenyl)-piperidin-4-yl}-methanol

A solution of the product of Example 6 (1.3 g) and piperidine (0.70 mL)in DCM (11 mL) was treated with sodium triacetoxyborohydride (1.9 g).After 16 h, the resulting mixture was treated with 10% aqueous potassiumhydroxide (10 mL). The aqueous phase was extracted with DCM (3×10 mL),and the combined organic phases were dried (MgSO₄), and concentratedunder reduced pressure, giving the title compound as a white waxy solid(1.5 g).

The compounds of Example 11 through Example 14 were prepared accordingto the procedure of Example 10, using the specified aldehydes andamines.

Example 11

{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-yl}-methanol

Prepared from the product of Example 6 and pyrrolidine.

Example 12

{1-(2-Morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-methanol

Prepared from the product of Example 7 and morpholine.

Example 13

{1-(4-Morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-methanol

Prepared from the product of Example 6 and morpholine.

Example 14

8-(4-Morpholin-4-ylmethyl-Phenyl)-1,4-dioxa-8-aza-spiro{4.5}decane

Prepared from the product of Example 8 and morpholine.

Example 15

1-(4:-Piperidin-1-ylmethyl-phenyl)-piperidine-4-carbaldehyde

A solution of oxalyl chloride (1.0 mL) in DCM (4 mL) was cooled in a−78° C. bath and treated with DMSO (0.17 mL). After 5 min, a solution ofthe product of Example 10 in DCM (2 mL) was added dropwise. After 30min, triethylamine (0.59 mL) was added, and the reaction mixture wasallowed to warm to room temperature. Water (2 mL) was added, and theresulting mixture was extracted with DCM (3×3 mL). The combined extractswere dried (MgSO₄) and concentrated under reduced pressure, giving thetitle compound, which was used without further purification.

The compounds of Example 16 through Example 18 were prepared accordingto the procedure of Example 15 using the specified alcohol.

Example 16

1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidine-4-carbaldehyde

Prepared from the product of Example 11.

Example 17

1-(2-Morpholin-4-ylmethyl-phenyl)-piperidine-4-carbaldehyde

Prepared from the product of Example 12.

Example 18

1-(4-Morpholin-4-ylmethyl-phenyl)-piperidine-4-carbaldehyde

Prepared from the product of Example 13.

Example 19

1-(4-Morpholin-4-ylmethyl-phenyl)-piperidin-4-one

The product of Example 14 (4.5 g) was treated with 6 M HCl (50 mL),heated to 100° C. for 90 min, and then cooled to room temperature. Theresulting solution was basified with 10% aqueous NaOH to pH 11, andextracted with DCM (3×5 mL). The combined extracts were dried (MgSO₄),and concentrated under reduced pressure, giving the title compound as abrown gummy solid (4.3 g).

Example 20

3-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzaldehyde

To a mixture of 3-formylphenylboronic acid (2.5 g) and piperidine (1.4g) in DCM (200 mL) was added 4 A molecular sieves (5 g) and copper(II)acetate (1.5 g) sequentially. The reaction mixture was stirred at roomtemperature for four days, filtered through a pad of Celite®, andconcentrated under reduced pressure. Purification of the residue bysilica gel chromatography (0-10% 2 M methanolic ammonia/DCM) affordedthe title compound as a yellow solid (0.79 g).

Example 21

1-(4:-Formyl-phenyl)-piperidine-4-carbaldehyde

Oxalyl chloride (2.5 mL, 2.0 M) was added to a cooled (−78° C.) solutionof DMSO (0.7 mL) in DCM (3 mL). After 20 min a solution of the productfrom Example 6 (0.38 g) in DCM (3 mL) was added. This mixture was agedfor an additional 20 min. Triethylamine was then added and the cold bath(CO₂/acetone) was removed. The mixture was allowed to reach ambienttemperature. After 1 h the mixture was poured into water (100 mL) andextracted with DCM. Removal of the solvent gave the title compound (0.38g), which was used without further purification.

Example 22

4-{2-(4:-Piperidin-1-ylmethyl-piperidin-1-yl)-benzyl}-morpholine

A solution of the product of Example 17 (288 mg) and piperidine (0.12mL) in dichloroethane (DCE, 2 mL) was treated with sodiumtriacetoxyborohydride (297 mg). After 16 h, the resulting mixture wastreated with 10% potassium hydroxide (2 mL), and extracted with DCM (2×2mL). The combined extracts were dried (MgSO₄), and chromatographed onsilica gel (0-8% 2 M methanolic ammonia/DCM), giving the title compoundas a colorless oil (100 mg).

¹H NMR (400 MHz, CDCl₃): 7.42 (dd, J=7.6, 1.6 Hz, 1H), 7.21 (t, J=8.0,1.8 Hz, 1H), 7.02 (ddd, J=8.0, 8.0, 1.0 Hz, 1H), 7.02 (ddd, J=7.4, 7.4,1.2 Hz, 1H), 3.68 (t, J=4.7 Hz, 4H), 3.54 (s, 2H), 3.21-3.15 (m, 2H),2.63 (ddd, J=11.7, 11.7, 2.2 Hz, 2H), 2.50-2.45 (br m, 4H), 2.41-2.37(br m, 4H), 2.22 (d, J=7.0 Hz, 2H), 1.85-1.79 (m, 2H), 1.70-1.56 (m,5H), 1.47-1.30 (m, 4H).

The compounds in Example 23 through Example 52 were prepared accordingto the procedure of Example 22 using the specified carbonyl compound andamine.

Example 23

Cyclohexyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine

Prepared from the product of Example 16 and cyclohexylamine.

¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.6 Hz, 2H), 6.90-6.87 (m, 2H), 3.66(d, J=12.2 Hz, 2H), 3.52 (s, 2H), 2.71-2.64 (m, 2H), 2.55 (d, J=6.7 Hz,4H), 2.49-2.43 (m, 4H), 2.42-2.36 (m, 1H), 1.90-1.53 (m, 11H), 1.41-1.01(m, 8H).

Example 24

1-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-azacyclotridecane

Prepared from the product of Example 16 and dodecamethyleneamine.

¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.6 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H),3.65 (d, J=12.3 Hz, 2H), 3.53 (s, 2H), 2.71-2.63 (m, 2H), 2.49 (br s,4H), 2.32-2.31 (m, 4H), 2.15 (d, J=6.9 Hz, 2H), 1.90 (d, J=13.0 Hz, 2H),1.79-1.73 (m, 4H), 1.63-1.24 (m, 23H).

Example 25

Diethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine

Prepared from the product of Example 16 and diethylamine.

¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H),3.65 (d, J=12.3 Hz, 2H), 3.52 (s, 2H), 2.70-2.64 (m, 2H), 2.53-2.48 (m,8H), 2.25 (d, J=7.0 Hz, 2H), 1.86 (d, J=12.5 Hz, 2H), 1.78-1.73 (m, 4H),1.58-1.51 (m, 1H), 1.36-1.26 (m, 2H), 1.01 (t, J=7.1 Hz, 6H).

Example 26

Dimethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine

Prepared from the product of Example 16 and dimethylamine hydrochloride.

¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H),3.66 (d, J=12.3 Hz, 2H), 3.53 (s, 2H), 2.71-2.64 (m, 2H), 2.48 (br s,4H), 2.22 (s, 6H), 2.15 (d, J=7.2 Hz, 2H), 1.85 (d, J=13.0 Hz, 2H),1.80-1.73 (m, 4H), 1.64-1.55 (m, 1H), 1.38-1.26 (m, 2H).

Example 27

1-Methyl-4-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperazine

Prepared from the product of Example 16 and N:-methylpiperazine.

¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.5 Hz, 2H),3.54 (s, 2H), 2.69-2.35 (m, 12H), 2.29 (s, 3H), 2.22 (d, J=7.2 Hz, 2H),1.87-1.59 (m, 9H), 1.38-1.26 (m, 2H).

Example 28

1-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidin-4-ol

Prepared from the product of Example 16 and 4-hydroxypiperidine.

¹H NMR (400 MHz, CDCl₃): 7.20 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.5 Hz, 2H),3.71-3.64 (m, 3H), 3.54 (s, 2H), 2.75-2.63 (m, 4H), 2.50 (br s, 4H),2.19 (d, J=7.8 Hz, 2H), 2.09 (t, J=10.1 Hz, 2H), 1.91-1.54 (m, 12H),1.38-1.24 (m, 3H).

Example 29

4-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-thiomorpholine

Prepared from the product of Example 16 and thiomorpholine.

¹H NMR (400 MHz, CDCl₃): 7.20 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H),3.65 (d, J=12.3 Hz, 2H), 3.53 (s, 2H), 3.14-3.10 (m, 1H), 2.71-2.58 (m,10H), 2.52-2.46 (m, 4H), 2.22 (d, J=7.0 Hz, 2H), 1.87-1.74 (m, 6H),1.68-1.56 (m, 2H), 1.31 (ddd, J=12.2 Hz, 12.2 Hz, 3.9 Hz, 2H).

Example 30

1-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine

Prepared from the product of Example 16 and piperidine.

¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.6 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H),3.65 (d, J=12.1 Hz, 2H), 3.53 (s, 2H), 2.65 (ddd, J=12.2, 12.2, 2.3 Hz,2H), 2.50-2.45 (m, 4H), 2.37-2.29 (br s, 2H), 2.16 (d, J=7.3 Hz, 2H),1.88-1.74 (m, 6H), 1.68-1.53 (m, 7H), 1.46-1.39 (m, 2H), 1.33 (dddd,J=12.2, 12.2, 12.2, 3.8 Hz, 2H).

Example 31

4-{1-(4:-Pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine

Prepared from the product of Example 16 and morpholine.

¹H NMR (400 MHz, CDCl₃): 7.20 (d, J=8.6 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H),3.71 (t, J=4.7 Hz, 4H), 3.66 (d, J=12.2 Hz, 2H), 3.53 (s, 2H), 2.69-2.63(m, 2H), 2.48 (br s, 4H), 2.43-2.41 (m, 4H), 2.22 (d, J=7.1 Hz, 2H),1.86 (d, J=12.4 Hz, 2H), 1.78-1.73 (m, 4H), 1.67-1.59 (m, 1H), 1.39-1.29(m, 2H).

Example 32

4-{3-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-thiomorpholine

Prepared from the product of Example 20 and thiomorpholine.

¹H NMR (400 MHz, CDCl₃): 7.21-7.17 (m, 1H), 6.90 (s, 1H), 6.85-6.76 (m,2H), 3.69 (d, J=12.3 Hz, 2H), 3.46 (s, 2H), 2.71-2.66 (m, 10H), 2.50 (brs, 4H), 2.36 (d, J=7.1 Hz, 2H), 1.90 (d, J=12.8 Hz, 2H), 1.82-1.75 (m,4H), 1.62-1.57 (m, 1H), 1.42-1.32 (m, 2H).

Example 33

4-{3-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-morpholine

Prepared from the product of Example 20 and morpholine.

¹H NMR (400 MHz, CDCl₃): 7.21-7.17 (m, 1H), 6.92 (s, 1H), 6.85-6.78 (m,2H), 3.72-3.67 (m, 6H), 3.45 (s, 2H), 2.72-2.65 (m, 2H), 2.49-2.44 (m,8H), 2.36 (d, J=7.1 Hz, 2H), 1.90 (d, J=12.8 Hz, 2H), 1.82-1.75 (m, 4H),1.67-1.58 (m, 1H), 1.42-1.32 (m, 2H).

Example 34

4:-Pyrrolidin-1-ylmethyl-1-(3-pyrrolidin-1-ylmethyl-phenyl)-piperidine

Prepared from the product of Example 20 and pyrrolidine.

¹H NMR (400 MHz, CDCl₃): 7.20-7.16 (m, 1H), 6.93 (s, 1H), 6.84-6.78 (m,2H), 3.69 (d, J=12.2 Hz, 2H), 3.57 (s, 2H), 2.71-2.64 (m, 2H), 2.50-2.49(m, 8H), 2.35 (d, J=7.2 Hz, 2H), 1.88 (d, J=13.1 Hz, 2H), 1.79-1.57 (m,9H), 1.41-1.25 (m, 2H).

Example 35

1-{3-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine

Prepared from the product of Example 20 and piperidine.

¹H NMR (400 MHz, CDCl₃): 7.20-7.16 (m, 1H), 6.92 (s, 1H), 6.84-6.77 (m,2H), 3.69 (d, J=12.3 Hz, 2H), 3.42 (s, 2H), 2.73-2.34 (m, 12H), 1.89 (d,J=12.9 Hz, 2H), 1.82-1.32 (m, 9H).

Example 36

1-{4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-azacyclotridecane

Prepared from the product of Example 9 and dodecamethyleneamine.

¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H),3.67 (d, J=12.2 Hz, 2H), 3.39 (s, 2H), 2.69-2.63 (m, 4H), 2.49 (br s,4H), 2.37-2.31 (m, 6H), 1.89 (d, J=12.1 Hz, 2H), 1.79-1.77 (m, 4H),1.63-1.35 (m, 21H).

Example 37

Cyclohexyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine

Prepared from the product of Example 9 and cyclohexylamine.

¹H NMR (400 MHz, CDCl₃): 7.18 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.6 Hz, 2H),3.71 (s, 2H), 3.66 (d, J=12.3 Hz, 2H), 2.69-2.63 (m, 2H), 2.50-2.46 (m,5H), 2.35 (d, J=7.2 Hz, 2H), 1.90-1.59 (m, 11H), 1.39-1.12 (m, 8H).

Example 38

1-{4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidin-4-ol

Prepared from the product of Example 9 and 4-hydroxypiperidine.

¹H NMR (400 MHz, CDCl₃): 7.26-7.15 (m, 2H), 6.88 (d, J=8.5 Hz, 2H),3.68-3.65 (m, 3H), 3.41 (s, 2H), 2.75-2.64 (m, 4H), 2.49-2.47 (m, 4H),2.35 (d, J=7.1 Hz, 2H), 2.10 (t, J=9.0 Hz, 2H), 1.90-1.75 (m, 10H),1.65-1.52 (m, 2H), 1.41-1.31 (m, 2H).

Example 39

1-Methyl-4-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperazine

Prepared from the product of Example 9 and N:-methylpiperazine.

¹H NMR (400 MHz, CDCl₃): 7.17 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H),3.66 (d, J=12.2 Hz, 2H), 3.42 (s, 2H), 2.73-2.31 (m, 14H), 2.27 (s, 3H),1.88 (br s, 4H), 1.82-1.75 (m, 4H), 1.65-1.57 (m, 1H), 1.41-1.31 (m,2H).

Example 40

4-{4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-thiomorpholine

Prepared from the product of Example 9 and thiomorpholine.

¹H NMR (400 MHz, CDCl₃): 7.15 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H),3.67 (d, J=12.2 Hz, 2H), 3.43 (s, 2H), 2.73-2.59 (m, 10H), 2.49 (br s,4H), 2.36 (d, J=7.2 Hz, 2H), 1.88 (d, J=13.3 Hz, 2H), 1.80-1.75 (m, 4H),1.67-1.57 (m, 1H), 1.41-1.31 (m, 2H).

Example 41

4-{4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-morpholine

Prepared from the product of Example 9 and morpholine.

¹H NMR (400 MHz, CDCl₃): 7.18 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.3 Hz, 2H),3.71-3.65 (m, 6H), 3.40 (s, 2H), 2.73-2.61 (m, 2H), 2.49 (br s, 4H),2.42 (bs, 4H), 2.36 (d, J=7.2 Hz, 2H), 1.88 (d, J=12.3 Hz, 2H),1.80-1.75 (m, 4H), 1.66-1.57 (m, 1H), 1.41-1.31 (m, 2H).

Example 42

Dimethyl-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine

Prepared from the product of Example 9 and dimethylamine hydrochloride.

¹H NMR (400 MHz, CDCl₃): 7.16 (d, J=8.6 Hz, 2H), 6.91-6.88 (m, 2H), 3.67(d, J=11.2 Hz, 2H), 3.33 (s, 2H), 2.70-2.64 (m, 2H), 2.52-2.47 (m, 4H),2.35 (d, J=7.1 Hz, 2H), 2.21 (s, 6H), 1.89 (d, J=12.9 Hz, 2H), 1.82-1.76(m, 4H), 1.65-1.56 (m, 1H), 1.42-1.32 (m, 2H).

Example 43

4-{2-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-morpholine

Prepared from the product of Example 17 and pyrrolidine.

¹H NMR (400 MHz, CDCl₃): 7.40 (dd, J=7.4, 1.6 Hz, 1H), 7.21 (dd, J=7.8,1.5 Hz, 2H), 7.06 (dd, J=8.0, 1.0 Hz, 1H), 7.02 (dd, J=7.4, 1.7 Hz, 1H),3.67 (t, J=4.7 Hz, 4H), 3.54 (s, 2H), 3.24-3.17 (m, 2H), 2.64 (ddd,J=11.7, 11.7, 2.1 Hz, 2H), 2.55-2.45 (m, 8H), 2.40 (m, 7.3 Hz, 2H),1.90-1.77 (m, 6H), 1.67-1.55 (m, 1H), 1.45-1.33 (m, 2H).

Example 44

4-{1-(4:-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-morpholine

Prepared from the product of Example 15 and morpholine.

¹H NMR (400 MHz, CDCl₃): 7.18 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H),3.71 (t, J=4.7 Hz, 4H), 3.66 (d, J=12.3 Hz, 2H), 3.39 (s, 2H), 2.69-2.63(m, 2H), 2.43-2.41 (m, 4H), 2.36 (br s, 4H), 2.22 (d, J=7.2 Hz, 2H),1.85 (d, J=12.7 Hz, 2H), 1.66-1.53 (m, 5H), 1.42-1.29 (m, 4H).

Example 45

1-{4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-piperidine

Prepared from the product of Example 15 and pyrrolidine.

¹H NMR (400 MHz, CDCl₃): 7.17 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H),3.66 (d, J=12.3 Hz, 2H), 3.39 (s, 2H), 2.66 (ddd, J=12.2, 12.2, 2.5 Hz,2H), 2.51-2.46 (m, 4H), 2.37-2.31 (m, 6H), 1.91-1.85 (m, 2H), 1.81-1.75(m, 4H), 1.65-1.52 (m, 5H), 1.45-1.31 (m, 4H).

Example 46

Cyclohexyl-{1-(4-morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-amine

Prepared from the product of Example 18 and cyclohexylamine.

¹H NMR (400 MHz, CDCl₃): 7.17 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H),3.71-3.61 (m, 6H), 3.40 (s, 2H), 2.78-2.70 (m, 3H), 2.65-2.55 (m, 1H),2.44-2.38 (m, 4H), 1.99-1.83 (m, 4H), 1.77-1.70 (m, 2H), 1.66-1.59 (m,1H), 1.51-1.39 (m, 2H), 1.32-1.01 (m, 6H).

Example 47

Cyclohexyl-methyl-{1-(4-morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-amine

Prepared from the product of Example 18 andN:-methyl:-N:-cyclohexylamine.

¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H),3.75-3.67 (m, 6H), 3.41 (s, 2H), 2.73-2.53 (m, 4H), 2.45-2.38 (m, 4H),2.28 (s, 3H), 1.89-1.59 (m, 9H), 1.35-1.19 (m, 4H), 1.16-1.04 (m, 1H).

Example 48

4-{4-{4-(4-Methyl-piperazin-1-yl)-piperidin-1-yl}-benzyl}-morpholine

Prepared from the product of Example 19 and N:-methylpiperazine.

¹H NMR (400 MHz, CDCl₃): 7.17 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H),3.76-3.66 (m, 6H), 3.40 (s, 2H), 2.69 (ddd, J=12.3, 12.3, 2.3 Hz, 2H),2.65-2.45 (m, 6H), 2.44-2.31 (m, 7H), 2.29 (s, 3H), 1.97-1.90 (m, 2H),1.72-1.60 (m, 2H).

Example 49

Ethyl-methyl-{1-(4-morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-amine

Prepared from the product of Example 19 and N:-methylethylamine.

¹H NMR (400 MHz, CDCl₃): 7.18 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H),3.76-3.67 (m, 6H), 3.49 (s, 3H), 3.41 (s, 2H), 2.68 (ddd, J=12.3, 12.3,2.4 Hz, 2H), 2.57 (q, J=7.3 Hz, 2H), 2.54-2.46 (m, 1H), 2.45-2.40 (m,4H), 1.90-1.84 (m, 2H), 1.74-1.62 (m, 2H), 1.08 (t, J=7.2 Hz, 3H).

Example 50

4-{1-(4-Morpholin-4-ylmethyl-phenyl)-piperidin-4-yl}-morpholine

Prepared from the product of Example 19 and morpholine.

¹H NMR (400 MHz, CDCl₃): 7.19 (d, J=8.6 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H),3.76-3.67 (m, 10H), 3.41 (s, 2H), 2.71 (ddd, J=12.2, 12.2, 2.4 Hz, 2H),2.61-2.56 (m, 4H), 2.45-2.39 (m, 4H), 2.36-2.27 (m, 1H), 1.98-1.90 (m,2H), 1.71-1.60 (m, 2H).

Example 51

4-{4-(4:-Pyrrolidin-1-yl-piperidin-1-yl)-benzyl}-morpholine

Prepared from the product of Example 19 and pyrrolidine.

¹H NMR (400 MHz, CDCl₃): 7.17 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H),3.71-3.64 (m, 6H), 3.40 (s, 2H), 2.73 (ddd, J=12.3, 2.5 Hz, 2H),2.62-2.57 (m, 4H), 2.44-2.37 (m, 4H), 2.15-2.06 (m, 1H), 2.02-1.95 (m,2H), 1.82-1.77 (m, 4H), 1.72-1.61 (m, 2H).

Example 52

1′-(4-Morpholin-4-ylmethyl-phenyl)-{1,4′}bipiperidinyl

Prepared from the product of Example 19 and piperidine.

¹H NMR (400 MHz, CDCl₃): 7.17 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H),3.77-3.67 (m, 6H), 3.41 (s, 2H), 2.67 (ddd, J=12.3, 12.3, 2.4 Hz, 2H),2.56-2.51 (m, 4H), 2.44-2.33 (m, 5H), 1.94-1.87 (m, 2H), 1.75-1.57 (m,6H), 1.48-1.41 (m, 2H).

Example 53

1′-(4:-Piperidin-1-ylmethyl-phenyl)-{1,4′}bipiperidinyl

Prepared from the product of Example 5 and piperidine.

¹H NMR (400 MHz, CDCl₃): 7.18 (m, 2H), 6.88 (m, 2H), 3.65 (m, 2H), 3.51(s, 2H), 2.65 (m, 2H), 2.50-2.44 (m, 8H), 2.34 (d, J=7.1 Hz, 2H), 1.87(br m, 2H), 1.81-1.71 (m, 8H), 1.65-1.53 (m, 1H), 1.41-1.30 (m, 2H).

Example 54

(4-{1,4′}Bipiperidinyl-1′-yl-benzyl)-pyridin-2-yl-amine

A solution of the product of Example 5 (109 mg), 2-aminopyridine (45mg), and acetic acid (0.05 mL) in DCE (1 mL) was treated with sodiumtriacetoxyborohydride (127 mg). After 16 h, the resulting mixture wastreated with 10% potassium hydroxide (1 mL), and extracted with DCM (2×1mL). The combined organic phases were dried (MgSO4) and chromatographedon silica gel (0-8% 2 M methanolic ammonia/DCM), giving the titlecompound (83 mg).

¹H NMR (400 MHz, CDCl₃): 8.10 (ddd, J=4.9, 1.8, 0.8 Hz, 1H), 7.39 (ddd,J=8.8, 7.0, 2.0 Hz, 1H), 7.23 (d, J=8.6 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H),6.57 (ddd, J=7.3, 5.1, 0.8 Hz, 1H), 6.37 (d, J=8.4 Hz, 1H), 4.77-4.71(m, 1H), 4.39 (d, J=5.5 Hz, 2H), 3.76-3.70 (m, 2H), 2.68 (ddd, J=12.3,12.3, 2.4 Hz, 2H), 2.56-2.51 (m, 4H), 2.42-2.34 (m, 1H), 1.94-1.87 (m,2H), 1.74-1.56 (m, 6H), 1.47-1.41 (m, 2H).

The compounds of Example 55 through Example 59 were prepared accordingto the procedure of Example 54 using the specified carbonyl compound andaminoarene.

Example 55

Phenyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine

Prepared from the product of Example 16 and aniline.

¹H NMR (400 MHz, CDCl₃): 7.21-7.16 (m, 4H), 6.89 (d, J=8.6 Hz, 2H),6.71-6.61 (m, 3H), 3.75-3.67 (m, 3H), 3.53 (s, 2H), 3.08-3.06 (m, 2H),2.72-2.65 (m, 2H), 2.48 (br s, 4H), 1.90 (d, J=12.3 Hz, 2H), 1.78-1.67(m, 5H), 1.50-1.40 (m, 2H).

Example 56

Pyridin-2-yl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine

Prepared from the product of Example 16 and 2-aminopyridine.

¹H NMR (400 MHz, CDCl₃): 8.09-8.07 (m, 1H), 7.44-7.39 (m, 1H), 7.20 (d,J=8.6 Hz, 2H), 6.91-6.88 (m, 2H), 6.58-6.55 (m, 1H), 6.39 (d, J=8.5 Hz,2H), 4.57 (br s, 1H), 3.69 (d, J=12.2 Hz, 2H), 3.53 (s, 2H), 3.22 (t,J=6.5 Hz, 2H), 2.72-2.65 (m, 2H), 2.50-2.47 (m, 4H), 1.92-1.70 (m, 5H),1.50-1.40 (m, 2H).

Example 57

1-{1-(4:-Piperidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-piperidine

A solution of the product of Example 21 (194.6 mg), piperidine (196 μL),and acetic acid (114 μL) in DCM (5 mL) was treated with sodiumtriacetoxyborohydride (570 mg). After 16 h, the resulting mixture wastreated with 10% sodium hydroxide (10 mL), and the mixture was extractedwith DCM (3×10 mL). The combined organic phases were dried (sodiumsulfate) and concentrated under reduced pressure. Chromatography of theresidue on silica gel (1-7% 2 M methanolic ammonia/DCM) gave the titlecompound (193.1 mg).

¹H NMR (400 MHz, CDCl₃): 7.16 (m, 2H), 6.87 (m, 2H), 3.73 (m, 2H), 3.39(s, 2H), 2.70-2.65 (m, 2H), 2.57-2.49 (br m, 4H), 2.41-2.29 (br, 5H),1.94-1.86 (br m, 2H), 1.75-1.51 (m, 10H), 1.48-1.37 (br m, 4H).

Example 58

4:-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidine

A solution of the product of Example 21 (185.5 mg), pyrrolidine (160μL), and acetic acid (114 μL) in DCM (5 mL) was treated with sodiumtriacetoxyborohydride (570 mg). After 16 h, the resulting mixture wastreated with 10% sodium hydroxide (10 mL), and the mixture was extractedwith DCM (3×10 mL). The combined organic phases were dried (sodiumsulfate) and concentrated under reduced pressure. Chromatography of theresidue on silica gel (1-7% 2 M methanolic ammonia/DCM) gave the titlecompound (114.1 mg).

¹H NMR (400 MHz, CDCl₃): 7.17 (m, 2H), 6.88 (m, 2H), 3.65 (m, 2H), 3.38(s, 2H), 2.65 (m, 2H), 2.39-2.28 (br m, 8H), 2.16 (d, J=7.1 Hz, 2H) 1.84(br m, 2H), 1.69-1.52 (m, 9H) 1.46-1.26 (m, 6H).

Example 59

(4:-Fluoro-phenyl)-{4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl}-amine

Prepared from the product of Example 9 and 4-fluoroaniline.

¹H NMR (400 MHz, CDCl₃): 7.23 (d, J=8.5 Hz, 2H), 6.92-6.84 (m, 4H),6.58-6.55 (m, 2H), 4.17 (d, J=2.4 Hz, 2H), 3.80 (br s, 1H), 3.68 (d,J=12.3 Hz, 2H), 2.71-2.65 (m, 2H), 2.49 (br s, 4H), 2.35 (d, J=7.2 Hz,2H), 1.88 (d, J=12.7 Hz, 2H), 1.82-1.77 (m, 4H), 1.65-1.57 (m, 1H),1.42-1.31 (m, 2H).

Example 60

4-{2-{1-(4:-Piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-morpholine

A solution of the product of the product of Example 10 (144 mg),morpholine (0.05 mL), N:-ethyl:-N,N:-diisopropylamine (0.17 mL), andtrimethyl-(cyanomethyl)phosphonium iodide (243 mg) in propionitrile (1mL) was heated in a 90° C. bath for 2 h. The resulting mixture wascooled to room temperature, treated with 10% aqueous potassium hydroxide(2 mL), and extracted with DCM (3×2 mL). The combined extracts weredried (MgSO₄) and chromatographed on silica gel (0-10% 2 M methanolicammonia/DCM), giving the title compound as a yellow oil (113 mg).

¹H NMR (400 MHz, CDCl₃): 7.14 (d, J=8.4 Hz, 2H), 6.48 (d, J=8.6 Hz, 2H),3.73 (t, J=4.7 Hz, 4H), 3.45 (dd, J=8.8, 7.6 Hz, 1H), 3.39 (s, 2H), 3.35(ddd, J=9.0, 9.0, 3.1 Hz, 1H), 3.27 (ddd, J=8.8, 8.8, 7.0 Hz, 1H), 2.91(dd, J=8.4, 8.4 Hz, 1H), 2.49-2.24 (m, 11H), 2.19-2.10 (m, 1H),1.70-1.53 (m, 7H), 1.45-1.37 (m, 2H).

The compounds of Example 61 and Example 62 were prepared according tothe procedure of Example 54 using the specified alcohol and secondaryamine.

Example 61

Diethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine

Prepared from the product of Example 10 and diethylamine.

¹H NMR (400 MHz, CDCl₃): 7.12 (d, J=8.4 Hz, 2H), 6.49 (d, J=8.6 Hz, 2H),3.45 (dd, J=8.2, 8.0 Hz, 1H), 3.34 (ddd, J=9.0, 9.0, 3.1 Hz, 1H), 3.27(ddd, J=9.0, 9.0, 6.9 Hz, 1H), 2.90 (dd, J=8.5, 8.5 Hz, 1H), 2.57-2.46(m, 6H), 2.40-2.31 (m, 4H), 2.30-2.22 (m, 2H), 2.19-2.11 (m, 1H),1.69-1.52 (m, 8H), 1.45-1.37 (m, 2H), 1.03 (t, J=7.1 Hz, 6H).

Example 62

Methyl-phenethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine

Prepared from the product of Example 10 and N:-methylphenethylamine.

¹H NMR (400 MHz, CDCl₃): 7.31-7.26 (m, 2H), 7.23-7.19 (m, 3H), 7.14 (d,J=8.6 Hz, 2H), 6.48 (d, J=8.6 Hz, 2H), 3.43 (dd, J=8.8, 7.6 Hz, 1H),3.34 (ddd, J=9.0, 9.0, 3.1 Hz, 1H), 3.26 (ddd, J=8.8, 8.8, 6.8 Hz, 1H),2.89 (dd, J=8.5, 8.5 Hz, 1H), 2.81-2.76 (m, 2H), 2.65-2.59 (m, 2H), 2.46(ddd, J=8.4, 7.3, 2.2 Hz, 2H), 2.46-2.32 (m, 4H), 2.32 (s, 3H),2.31-2.20 (m, 2H), 2.17-2.08 (m, 1H), 1.68-1.52 (m, 8H), 1.45-1.37 (m,2H).

The compounds of Example 63 through Example 67 were prepared accordingto the procedure of Example 6 using the specified fluorobenzaldehyde.

Example 63

4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-3-trifluoromethyl-benzaldehyde

Prepared from the product of Example 4 and4-fluoro-3-trifluoromethyl-benzaldehyde.

Example 64

3:-Nitro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzaldehyde

Prepared from the product of Example 4 and4-fluoro-3-nitro-benzaldehyde.

Example 65

4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-2-trifluoromethyl-benzaldehyde

Prepared from the product of Example 4 and4-fluoro-2-trifluoromethyl-benzaldehyde.

Example 66

3-Methyl-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzaldehyde

Prepared from the product of Example 4 and4-fluoro-3-methyl-benzaldehyde.

Example 67

3:-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzaldehyde

Prepared from the product of Example 4 and 3,4-difluorobenzaldehyde.

The compounds of Example 68 through 81 were prepared according to theprocedure of Example 22 from the specified carbonyl compound and amine.

Example 68

1-[4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-3-trifluoromethyl-benzyl]-piperidine

Prepared from the product of Example 63 and piperidine.

¹H NMR (400 MHz, CDCl₃): 7.43 (d, J=1.9 Hz, 1H), 7.35 (dd, J=8.2, 1.6Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 3.34 (s, 2H), 2.97 (d, J=11.5 Hz, 2H),2.59 (tt, J=11.3, 2.0 Hz, 2H), 2.48-2.40 (m, 4H), 2.33-2.22 (m, 6H),1.77-1.66 (m, 6H), 1.55-1.43 (m, 5H), 1.39-1.26 (m, 4H).

Example 69

1-(2:-Nitro-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-piperidine

Prepared from the product of Example 64 and piperidine.

¹H NMR (400 MHz, CDCl₃): 7.68 (d, J=2.0, 1H), 7.4 (dd, J=8.4, 2.2 Hz,1H), 7.06 (d, 8.4 Hz, 1H), 3.40 (s, 2H), 3.26 (d, J=12.3 Hz, 2H), 2.79(tt, J=11.9, 2.2 Hz, 2H), 2.54-2.44 (m, 4H), 2.42-2.26 (m, 6H),1.88-1.74 (m, 6H), 1.6-1.5 (m, 5H), 1.48-1.36 (m, 4H).

Example 70

4-[3:-Nitro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-morpholine

Prepared from the product of Example 64 and morpholine.

¹H NMR (400 MHz, CDCl₃): 7.71 (d, J=2.0 Hz, 1H), 7.74 (dd, J=8.4, 2.2Hz, 1H), 7.06 (d, J=8.6, 1H), 3.69 (t, J=4.5 Hz, 4H), 3.43 (s, 2H), 3.26(d, J=12.3, 2H), 2.79 (tt, J=12.0, 2.1 Hz, 2H), 2.54-2.45 (m, 4H),2.45-2.39 (m, 4H), 2.39-2.32 (m, 2H), 1.88-1.72 (m, 6H), 1.68-1.34 (m,1H), 1.48-1.34 (m, 2H).

Example 71

1-[3:-Nitro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidin-4-ol

Prepared from the product of Example 64 and 4-hydroxypiperidine.

¹H NMR (400 MHz, CDCl₃): 7.69 (d, J=2.0 Hz, 1H), 7.40 (dd, J=8.4, 2.1Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 3.70 (m, 1H), 3.43 (s, 2H), 3.26 (d,J=12.0 Hz, 2H), 2.79 (tt, J=12.0, 2.4 Hz, 2H), 2.73-2.70 (m, 2H),2.50-2.45 (m, 4H), 2.36 (d, J=6.8 Hz, 2H), 2.14 (t, J=10.4 Hz, 2H),1.90-1.75 (m, 8H), 1.62-1.54 (m, 4H), 1.46-1.39 (m, 2H).

Example 72

1-[4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-2-trifluoromethyl-benzyl]-piperidine

Prepared from the product of Example 65 and 4-hydroxypiperidine.

¹H NMR (400 MHz, CDCl₃): 7.60 (d, J=8.6 Hz, 1H), 7.13 (d, J=2.6 Hz, 1H),7.04 (dd, J=8.6, 2.5 Hz, 1H), 3.68 (d, J=12.3 Hz, 2H), 3.66 (s, 2H),2.70 (tt, J=12.2, 2.5 Hz, 2H), 2.5-2.48 (m, 4H), 2.4-2.3 (m, 6H), 1.91(d, J=1.1, 2H), 1.85-1.70 (m, 4H), 1.70-1.50 (m, 5H), 1.50-1.20 (m, 4H).

Example 73

1:-Isopropyl-4-[3-methyl-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperazine

Prepared from the product of Example 66 and 1-isopropylpiperazine.

¹H NMR (400 MHz, CDCl₃): 7.10 (d, J=1.6 Hz, 1H), 7.06 (dd, J=8.0, 1.9Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 3.42 (s, 2H), 3.10 (d, J=9.1 Hz, 2H),2.7-2.2 (m, 15H), 2.1-1.7 (m, 11H), 1.66-1.53 (m, 1H), 1.5-1.3 (m, 2H),1.04 (d, J=6.5 Hz, 6H).

Example 74

1-(2-Methyl-4-pyrrolidin-1-ylmethyl-phenyl)-4-pyrrolidin-1-ylmethyl-pyrrolidine

Prepared from the product of Example 66 and pyrrolidine.

¹H NMR (400 MHz, CDCl₃): 7.13 (d, J=2.0 Hz, 1H), 7.07 (dd, J=8.2, 2.0Hz, 1H), 6.93 (d, J=8.2 Hz, 1H), 3.52 (s, 2H), 3.10 (d, J=12.1, 2H),2.59 (tt, J=12.1, 2.2 Hz, 2H), 2.54-2.44 (m, 8H), 2.41-2.37 (m, 2H),2.26 (s, 3H), 1.89-1-81 (m, 2H), 1.81-1.72 (m, 8H), 1.65-1.52 (m, 1H),1.45-1.31 (m, 2H).

Example 75

1-[3-Methyl-4-(4-pyrrolidin-1-vymethyl-piperidin-1-yl)-benzyl]-pyrrolidine

Prepared from the product of Example 66 and piperidine.

¹H NMR (400 MHz, CDCl₃): 7.10 (d, J=1.8 Hz, 1H), 7.06 (dd, J=8.0, 1.8Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 3.38 (s, 2H), 3.11 (d, 2H), 2.65-2.54(m, 2H), 2.54-2.43 (m, 4H), 2.42-2.29 (m, 6H), 2.27 (s, 3H), 1.90-1.81(m, 2H), 1.81-1.71 (m, 4H), 1.66-1.50 (m, 5H), 1.47-1.31 (m, 4H).

Example 76

1-{1-[4-(4:-Pyrrolidin-1-yl-piperidin-1-ylmethyl)-2-trifluoromethyl-phenyl]-piperidin-4-ylmethyl}-pyrrolidine

Prepared from the product of Example 63 and4:-N:-pyrrolidinylpiperidine.

¹H NMR (400 MHz, CDCl₃): 7.52 (d, J=1.5 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H),7.28-7.25 (m, 1H), 3.45 (s, 2H), 3.05 (d, J=11.4 Hz, 2H), 2.84 (d,J=11.7 Hz, 2H), 2.68 (t, J=11.3 Hz, 2H), 2.63-2.44 (m, 8H), 2.38 (d,J=7.0, 2H), 2.10-1.91 (m, 3H), 1.91-1.70 (m, 12H), 1.49-1.33 (m, 2H).

Example 77

1-(1-{3-Trifluoromethyl-4-[4-(4-trifluoromethyl-phenyl)-piperidin-1-ylmethyl]-phenyl}-piperidin-4-ylmethyl)-pyrrolidine

Prepared from the product of Example 65 and4-(4-trifluouromethylphenyl)-piperidine.

¹H NMR (500 MHz, CDCl₃): 7.62 (d, J=8.6 Hz, 1H), 7.54 (d, J=8.0 Hz, 2H),7.34 (d, J=8.2 Hz, 2H), 7.14 (d, J=2.5 Hz, 1H), 7.01 (dd, J=8.1, 2.5 Hz,1H), 3.70 (d, J=12.3 Hz, 2H), 3.58 (s, 2H), 2.98 (d, J=11.7 Hz, 2H),2.88-2.34 (m, 8H), 2.31-1.56 (m, 13H), 1.52-1.05 (m, 3H).

Example 78

1-{1-[2:-Fluoro-4-(4-phenyl-piperidin-1-ylmethyl)-phenyl]-piperidin-4-ylmethyl}-pyrrolidine

Prepared from the product of Example 67 and 4-phenylpiperidine.

¹H NMR (500 MHz, CDCl₃): 7.37-7.16 (m, 5H), 7.12-6.87 (m, 3H), 3.53-3.41(m, 4H), 3.01 (d, J=11.5 Hz, 2H), 2.67 (t, J=11.5, 9.9 Hz, 2H),2.58-2.45 (m, 5H), 2.40 (d, J=7.1, 2H), 2.14-2.01 (m, 2H), 1.97-1.87 (m,2H), 1.86-1.73 (m, 8H), 1.69-1.56 (m, 1H), 1.54-1.41 (m, 2H).

Example 79

[3:-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-dimethyl-amine

Prepared from the product of Example 67 and dimethylamine hydrochloride.

¹H NMR (500 MHz, CDCl₃): 7.00-6.93 (m, 2H), 6.90-6.87 (m, 1H), 3.46-3.40(m, 2H), 3.33 (s, 2H), 2.67-2.59 (m, 2H), 2.57-2.54 (m, 4H), 2.38 (d,J=7.1 Hz, 2H), 2.21 (s, 6H), 1.91-1.84 (m, 2H), 1.81-1.75 (m, 4H),1.66-1.55 (m, 1H), 1.49-1.38 (m, 2H).

Example 80

1-[3:-Fluoro-4-(4-pyrrolidin-1-ylmethyl-piperidin-1-yl)-benzyl]-piperidine

Prepared from the product of Example 67 and piperidine.

¹H NMR (500 MHz, CDCl₃): 6.94-6.87 (m, 2H), 6.80 (t, J=8.6, 1H), 3.35(d, J=12.0 Hz, 2H), 3.30 (s, 2H), 2.57-2.43 (m, 2H), 2.43-2.27 (m, 11H),1.73-1.70 (m, 6H), 1.51-1.34 (m, 8H).

Example 81

13-[4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-2-trifluoromethyl-benzyl]-1,4,7,10-tetraoxa-13-aza-cyclopentadecaneditrifluoromethanesulfonate

Prepared from the product of Example 65 and1,4,7,10-tetraoxa-13-aza-cyclopentadecane. The crude material waspurified by HPLC (Column: Phenomenex, Synergi Max-RP C-12; 4 micronparticle size; 100 mm×21.2 mm (ID) mm. Gradient System: 10%water:acetonitrile to 99% water:acetonitrile containing 0.05% TFA over0-19 minutes) to provide the target compound as theditrifluoromethanesulfonate salt.

¹H NMR (500 MHz, CD₃OD): 7.68 (d, J=8.7 Hz, 1H), 7.29 (d, J=2.6 Hz, 1H),7.26 (dd, J=8.7, 2.6 Hz, 1H), 3.95-2.92 (m, 31H), 2.17-1.93 (m, 8H),1.45-1.40 (m, 2H).

Example 82

{1-[4-(4:-Pyrrolidin-1-ylmethyl-piperidin-1-yl)-3-trifluoromethyl-benzyl]-piperidin-4-yl}-methanol

Prepared from the product of Example 63 and 4-hydroxymethylpiperidine.

¹H NMR (500 MHz, CDCl₃): 7.78-7.14 (m, 3H), 4.30-4.11 (m, 1H), 3.52-3.44(m, 2H), 3.15-2.49 (m, 7H), 2.06-1.60 (m, 11H), 1.56-0.75 (m, 12H).

Biological Methods In Vitro

Transfection of cells with human histamine receptor

A 10 cm tissue culture dish with a confluent monolayer of SK-N-MC cellswas split two days prior to transfection. Using sterile technique themedia was removed and the cells were detached from the dish by theaddition of trypsin. One fifth of the cells were then placed onto a new10 cm dish. Cells were grown in a 37° C. incubator with 5% CO₂ inMinimal Essential Media Eagle with 10% Fetal Bovine Serum. After twodays cells were approximately 80% confluent. These were removed from thedish with trypsin and pelleted in a clinical centrifuge. The pellet wasthen re-suspended in 400 μL complete media and transferred to anelectroporation cuvette with a 0.4 cm gap between the electrodes. Onemicrogram of supercoiled H₃ receptor cDNA was added to the cells andmixed. The voltage for the electroporation was set at 0.25 kV, thecapacitance was set at 960 μF. After electroporation the cells werediluted into 10 mL complete media and plated onto four 10 cm dishes.Because of the variability in the efficiency of electroporation, fourdifferent concentrations of cells were plated. The ratios used were;1:20, 1:10, 1:5, with the remainder of the cells being added to thefourth dish. The cells were allowed to recover for 24 h before addingthe selection media (complete media with 600 μg/mL G418). After 10 daysdishes were analyzed for surviving colonies of cells. Dishes withwell-isolated colonies were used. Cells from individual colonies wereisolated and tested. SK-N-MC cells were used because they give efficientcoupling for inhibition of adenylate cyclase. The clones that gave themost robust inhibition of adenylate cyclase in response to histaminewere used for further study.

{³H}-N-methylhistamine binding

Cell pellets from histamine H₃ receptor-expressing SK-N-MC cells werehomogenized in 20 mM Tris HCl/0.5 mM EDTA. Supernatants from an 800 gspin were collected, recentrifuged at 30,000 g for 30 min. Pellets werere-homogenized in 50 mM Tris/5 mM EDTA (pH 7.4). Membranes wereincubated with 0.8 nM {³H}:-N:-methylhistamine plus/minus test compoundsfor 45 min at 25° C. and harvested by rapid filtration over GF/C glassfiber filters (pretreated with 0.3% polyethylenimine) followed by fourwashes with ice-cold buffer. Filters were dried, added to 4 mLscintillation cocktail and then counted on a liquid scintillationcounter. Non-specific binding was defined with 10 μM histamine. ThepK_(i) values were calculated based on a K_(d) of 800 μM and a ligandconcentration ({L}) of 800 μM according to the formula:K _(i)=(IC ₅₀)/(1+({L}/(K _(d)))

K_(i) values for exemplary compounds of the invention are listed in thetable below: EX K_(i) (nM) 22 4500 23 0.9 24 23 25 0.8 26 1.7 27 1.4 280.8 29 2 30 1.0 31 2.0 32 9.0 33 20 34 6.0 35 10 36 6.0 37 2.0 38 5.0 396.0 40 4.0 41 12 42 5.0 43 4800 44 5.0 45 2.0 46 28 47 5.8 48 1000 49 1450 272 51 17 52 5.5 53 2.7 54 8.4 55 8.0 56 3.0 57 2.5 58 0.6 59 48 601.1 61 0.8 62 1.3 68 14 69 2 70 36 71 5 72 8 73 16 74 1 75 6 76 9 77 16078 7 79 4 80 4 81 34 82 170

F. OTHER EMBODIMENTS

The features and advantages of the invention will be apparent to one ofordinary skill in view of the discussion, examples, embodiments, andclaims relating to the invention. The invention also contemplatesvariations and adaptations, based on the disclosure herein concerningthe key features and advantages of the invention, and within theabilities of one of ordinary skill.

1. A composition comprising a compound of formula (I):

Wherein L is a direct bond, or an optionally C₁₋₄alkyl substitutedradical selected from the group consisting of C₁₋₄alkylene orC₃₋₄alkenylene wherein NR¹R² is attached to an Sp³ hybridized carbon,C₃₋₄alkynylene wherein NR¹R² is attached to an Sp³ hybridized carbon,C₂₋₄alkylidene wherein NR¹R² is attached to an Sp³ hybridized carbon,aryloxy wherein NR¹R² is not attached to the oxygen, arylthio whereinNR¹R² is not attached to the sulfur, C₂₋₄alkoxy wherein NR¹R² is notattached to the oxygen or a carbon attached to the oxygen, C₂₋₄alkylthiowherein NR¹R² is not attached to the sulfur or a carbon attached to thesulfur, and —C₂₋₃alkyl-X—C₁₋₂alkyl- wherein X is O, S or NH and whereinNR¹R² is not attached to a carbon attached to X; p is 0, 1 or 2; q is 1or 2; provided that 2≦p+q≦4; R¹ is a substituent independently selectedfrom the group consisting of hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₉carbocyclyl, pyridinyl, phenyl, pyridinylC₁₋₆ alkylene, and (phenyl)C₁₋₆alkylene; R² is a substituent independently selected from the groupconsisting of C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₉ membered carbocyclyl,pyridinyl, phenyl, pyridinylC₁₋₆ alkylene, and (phenyl)C₁₋₆ alkylene;wherein R¹ and R² are optionally and independently substituted with 1-3substituents selected from the group consisting oftert-butyloxycarbonyl, hydroxy, halo, nitro, amino, cyano, carboxamide,C₁₋₆ alkyl, C₁₋₆ acyl, 5-9-membered heterocyclyl, —N(C₁₋₆ alkyl)(5-9membered heterocyclyl), —NH(5-9 membered heterocyclyl), —O(5-9 memberedheterocyclyl), (5-9 membered heterocyclyl)C₁₋₃ alkylene,C₁₋₁₂-hydroxyalkylene, C₁₋₆ alkoxy, (C₃₋₆ cycloalkyl):-O—, phenyl,(phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃ alkylene-O—; and wherein each ofthe preceding substituents of R¹ and R² may optionally have between 1and 3 substituents independently selected from the group consisting oftrifluoromethyl, halo, nitro, cyano, hydroxy, and C₁₋₃ alkyl; one of R³,R⁴ and R⁵ is G and the other two independently are hydrogen, fluoro,chloro, bromo, nitro, trifluoromethyl, methyl, or C₁₋₃ alkoxy; G is L²Q;L² is unbranched —(CH₂)_(n)— wherein n is an integer from 1 to 7; Q is aN:-linked heterocyclyl which is piperidinyl or pyrrolidinyl; wherein Qis optionally substituted with 1-3 substituents selected (in addition tothe preceding paragraph) from the group consisting oftert-butyloxycarbonyl, hydroxy, halo, nitro, amino, cyano, carboxamide,C₁₋₆ alkyl, C₁₋₆ acyl, 5-9-membered heterocyclyl, —N(C₁₋₆ alkyl)(5-9membered heterocyclyl), —NH(5-9 membered heterocyclyl), —O(5-9 memberedheterocyclyl), (5-9 membered heterocyclyl)C₁₋₃ alkylene,C₁₋₂-hydroxyalkylene, C₁₋₆ alkoxy, (C₃₋₆ cycloalkyl):-O—, phenyl,(phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃ alkylene-O—; and where saidsubstituent groups of Q may optionally have between 1 and 3 substituentsindependently selected from trifluoromethyl, halo, nitro, cyano,hydroxy, and C₁₋₃ alkyl; R^(a) are independently C₁₋₃ alkyl,trifluoromethyl; m is 0, 1, 2 or 3; and wherein each of the above alkyl,alkylene, alkenyl, heterocyclyl, cycloalkyl, carbocyclyl, and arylgroups may each be independently and optionally substituted with between1 and 3 substituents independently selected from methoxy, halo, amino,nitro, hydroxy, and C₁₋₃ alkyl; or a pharmaceutically acceptable acidaddition alkali metal or alkaline earth metal salt, thereof. 2.(canceled)
 3. (canceled)
 4. (canceled)
 5. (canceled)
 6. (canceled) 7.(canceled)
 8. (canceled)
 9. (canceled)
 10. (canceled)
 11. (canceled) 12.(canceled)
 13. (canceled)
 14. A compound of claim 1, wherein one of R³and R⁴ is G.
 15. A compound of claim 14, wherein R⁴ is G.
 16. A compoundof claim 14, wherein R³ is G.
 17. A compound of claim 1, wherein q is 2and p is
 1. 18. A compound of claim 1, wherein q is 1 and p is
 1. 19. Acompound of claim 1, wherein q is 2 and p is
 2. 20. A compound of claim1, wherein 1, is —CH₂—.
 21. A compound of claim 1, wherein 1, is adirect bond.
 22. A compound of claim 1, wherein 1, is —CH₂CH₂—.
 23. Acompound of claim 1, wherein L² is —CH₂—.
 24. (canceled)
 25. (canceled)26. (canceled)
 27. (canceled)
 28. (canceled)
 29. A compound of claim 1,wherein Q is optionally substituted with between 1 and 3 substituentsselected from hydroxy, halo, carboxamide, C₁₋₆ alkyl, C₁₋₆ acyl, 5-9membered or 6-9 membered heterocyclyl, —N(C₁₋₆ alkyl)(5-9 membered or6-9 membered heterocyclyl), —NH(5-9 membered or 6-9 memberedheterocyclyl), —O(5-9 or 6-9 membered heterocyclyl), (5-9 membered or6-9 membered heterocyclyl)C₁₋₃ alkylene, C₁₋₁₂-hydroxyalkylene, C₁₋₆alkoxy, (C₃₋₆ cycloalkyl):-O—, phenyl, (phenyl)C₁₋₃ alkylene, and(phenyl)C₁₋₃ alkylene-O— where each of above heterocyclyl, phenyl, andalkyl groups may be optionally substituted with from 1 to 3 substituentsindependently selected from trifluoromethyl, halo, nitro, cyano,hydroxy, and C₁₋₃ alkyl.
 30. A compound of claim 29, wherein Q issubstituted with a substituent comprising a 5-9 membered heterocyclylgroup selected from: pyridyl, pyrimidyl, furyl, thiofuryl, imidazolyl,(imidazolyl)C₁₋₆ alkylene, oxazolyl, thiazolyl, 2,3-dihydro-indolyl,benzimidazolyl, 2-oxobenzimidazolyl, (tetrazolyl)C₁₋₆ alkylene,tetrazolyl, (triazolyl)C₁₋₆ alkylene, triazolyl, (pyrrolyl)C₁₋₁₆alkylene, pyrrolidinyl, and pyrrolyl.
 31. (canceled)
 32. (canceled) 33.(canceled)
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 37. (canceled)38. (canceled)
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 41. (canceled) 42.(canceled)
 43. (canceled)
 44. (canceled)
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 46. A compoundof claim 1, wherein Q is piperidinyl or substituted piperidinyl. 47.(canceled)
 48. A compound of claim 1 wherein R^(a) is hydrogen.
 49. Acompound of claim 1 selected from the group consisting ofCyclohexyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;Diethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;Dimethyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;Phenyl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;Pyridin-2-yl-{1-(4-pyrrolidin-1-ylmethyl-phenyl)-piperidin-4-ylmethyl}-amine;Diethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine;andMethyl-phenethyl-{2-{1-(4-piperidin-1-ylmethyl-phenyl)-pyrrolidin-3-yl}-ethyl}-amine.50. (canceled)
 51. (canceled)
 52. (canceled)
 53. (canceled)
 54. Apharmaceutical composition, comprising a compound of claim 1 and apharmaceutically-acceptable excipient.
 55. (canceled)
 56. (canceled) 57.(canceled)
 58. (canceled)
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 61. (canceled)62. (canceled)
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 65. (canceled) 66.(canceled)
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 68. (canceled)